Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance

Journal of Perinatology volume 34, pages 549–554 (2014)Cite this article

Subjects

Abstract

Objective:

Necrotizing enterocolitis (NEC) is characterized by macrophage infiltration into affected tissues. Because intestinal macrophages are derived from recruitment and in situ differentiation of blood monocytes in the gut mucosa, we hypothesized that increased recruitment of monocytes to the intestine during NEC reduces the blood monocyte concentration and that this fall in blood monocytes can be a useful biomarker for NEC.

Study Design:

We reviewed medical records of very-low-birth-weight (VLBW) infants treated for NEC and compared them with a matched control group comprised of infants with feeding intolerance but no signs of NEC. Clinical characteristics and absolute monocyte counts (AMCs) were recorded. Diagnostic accuracy of AMC values was tested using receiver–operator characteristics (ROC).

Result:

We compared 69 cases and 257 controls (median 27 weeks, range 26 to 29 in both the groups). In stage II NEC, AMCs decreased from median 1.7 × 109 l−1 (interquartile range (IQR) 0.98 to 2.4) to 0.8 (IQR 0.62 to 2.1); P<0.05. In stage III NEC, monocyte counts decreased from median 2.1 × 109 l−1 (IQR 0.1.5 to 3.2) to 0.8 (IQR 0.6 to 1.9); P<0.05. There was no change in AMCs in control infants. ROC of AMC values showed a diagnostic accuracy (area under the curve) of 0.76. In a given infant with feeding intolerance, a drop in AMCs of >20% indicated NEC with sensitivity of 0.70 (95% confidence interval (CI) 0.57 to 0.81) and specificity of 0.71 (95% CI 0.64 to 0.77).

Conclusion:

We have identified a fall in blood monocyte concentration as a novel biomarker for NEC in VLBW infants.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Neu J, Walker WA . Necrotizing enterocolitis. N Engl J Med 2011; 364: 255–264.

    Article  CAS  Google Scholar 

  2. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007; 196: 147 e141–147 e148.

    Article  Google Scholar 

  3. Buonomo C . The radiology of necrotizing enterocolitis. Radiol Clin North Am 1999; 37: 1187–1198 vii.

    Article  CAS  Google Scholar 

  4. Walsh MC, Kliegman RM . Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33: 179–201.

    Article  CAS  Google Scholar 

  5. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F . Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 2003; 6: 6–23.

    Article  Google Scholar 

  6. Coursey CA, Hollingsworth CL, Gaca AM, Maxfield C, Delong D, Bisset G 3rd . Radiologists' agreement when using a 10-point scale to report abdominal radiographic findings of necrotizing enterocolitis in neonates and infants. Am J Roentgenol 2008; 191: 190–197.

    Article  Google Scholar 

  7. Coursey CA, Hollingsworth CL, Wriston C, Beam C, Rice H, Bisset G 3rd . Radiographic predictors of disease severity in neonates and infants with necrotizing enterocolitis. Am J Roentgenol 2009; 193: 1408–1413.

    Article  Google Scholar 

  8. Lin PW, Stoll BJ . Necrotising enterocolitis. Lancet 2006; 368: 1271–1283.

    Article  Google Scholar 

  9. Holman RC, Stoll BJ, Curns AT, Yorita KL, Steiner CA, Schonberger LB . Necrotising enterocolitis hospitalisations among neonates in the United States. Paediatr Perinat Epidemiol 2006; 20: 498–506.

    Article  Google Scholar 

  10. Mohankumar K, Kaza N, Jagadeeswaran R, Garzon SA, Bansal A, Kurundkar AR et al. Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model. Am J Physiol Gastrointest Liver Physiol 2012; 303: G93–G102.

    Article  CAS  Google Scholar 

  11. Pender SL, Braegger C, Gunther U, Monteleone G, Meuli M, Schuppan G . Matrix metalloproteinases in necrotising enterocolitis. Pediatr Res 2003; 54: 160–164.

    Article  CAS  Google Scholar 

  12. Halpern MD, Holubec H, Dominguez JA, Williams CS, Meza YG, McWilliam DL et al. Up-regulation of IL-18 and IL-12 in the ileum of neonatal rats with necrotizing enterocolitis. Pediatr Res 2002; 51: 733–739.

    Article  CAS  Google Scholar 

  13. Halpern MD, Khailova L, Molla-Hosseini D, Arganbright K, Reynolds C, Yajima M et al. Decreased development of necrotizing enterocolitis in IL-18-deficient mice. Am J Physiol Gastrointest Liver Physiol 2008; 294: G20–G26.

    Article  CAS  Google Scholar 

  14. Maheshwari A, Kurundkar AR, Shaik SS, Kelly DR, Hartman Y, Zhang W et al. Epithelial cells in fetal intestine produce chemerin to recruit macrophages. Am J Physiol Gastrointest Liver Physiol 2009; 297: G1–G10.

    Article  CAS  Google Scholar 

  15. Smythies LE, Maheshwari A, Clements R, Eckhoff D, Novak L, Vu HL et al. Mucosal IL-8 and TGF-beta recruit blood monocytes: evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leukoc Biol 2006; 80: 492–499.

    Article  CAS  Google Scholar 

  16. Christensen RD, Jensen J, Maheshwari A, Henry E . Reference ranges for blood concentrations of eosinophils and monocytes during the neonatal period defined from over 63 000 records in a multihospital health-care system. J Perinatol 2010; 30: 540–545.

    Article  CAS  Google Scholar 

  17. van Furth R, Sluiter W . Distribution of blood monocytes between a marginating and a circulating pool. J Exp Med 1986; 163: 474–479.

    Article  CAS  Google Scholar 

  18. Murphy MF, Brozovic B, Murphy W, Ouwehand W, Waters AH . Guidelines for platelet transfusions. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force. Transfus Med 1992; 2: 311–318.

    Article  CAS  Google Scholar 

  19. Giles LG . Evidence-based clinical guidelines submitted to the Australian National Health and Medical Research Council for the management of acute low back pain: a critical review. J Manipulative Physiol Ther 2001; 24: 131–139.

    Article  CAS  Google Scholar 

  20. Spinella PC, Dressler A, Tucci M, Carroll CL, Rosen RS, Hume H et al. Survey of transfusion policies at US and Canadian children's hospitals in 2008 and 2009. Transfusion 2010; 50: 2328–2335.

    Article  Google Scholar 

  21. Contreras M, Ala FA, Greaves M, Jones J, Levin M, Machin SJ et al. Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force. Transfus Med 1992; 2: 57–63.

    Article  CAS  Google Scholar 

  22. Wright SE, McKay R, Taylor KI, Keeffe JE, McCarty CA . Changes in attitudes and practices of optometrists in their management of diabetic retinopathy after the release of NHMRC guidelines. National Health and Medical Research Council. Clin Ophthalmol 2001; 29: 121–124.

    Article  CAS  Google Scholar 

  23. Shih W . Problems in dealing with missing data and informative censoring in clinical trials. Curr Control Trials Cardiovasc Med 2002; 3: 4.

    Article  Google Scholar 

  24. Practice guidelines for blood component therapy: a report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; 84: 732–747.

  25. Diggle PJ, Liyang KY, Zeger SL . Analysis of Longitudinal Data. Clarendon Press: Oxford, UK, 1994.

    Google Scholar 

  26. Zweig MH, Campbell G . Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993; 39: 561–577.

    CAS  PubMed  Google Scholar 

  27. Yardeni T, Eckhaus M, Morris HD, Huizing M, Hoogstraten-Miller S . Retro-orbital injections in mice. Lab Anim 2011; 40: 155–160.

    Article  Google Scholar 

  28. Newcombe RG . Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998; 17: 857–872.

    Article  CAS  Google Scholar 

  29. Chaaban H, Shin M, Sirya E, Lim YP, Caplan M, Padbury JF . Inter-alpha inhibitor protein level in neonates predicts necrotizing enterocolitis. J Pediatr 2010; 157: 757–761.

    Article  CAS  Google Scholar 

  30. Edelson MB, Sonnino RE, Bagwell CE, Lieberman JM, Marks WH, Rozycki HJ . Plasma intestinal fatty acid binding protein in neonates with necrotizing enterocolitis: a pilot study. J Pediatr Surg 1999; 34: 1453–1457.

    Article  CAS  Google Scholar 

  31. Lobe TE, Richardson CJ, Rassin DK, Mills R, Schwartz M . Hexosaminidase: a biochemical marker for necrotizing enterocolitis in the preterm infant. Am J Surg 1984; 147: 49–52.

    Article  CAS  Google Scholar 

  32. Lobe TE, Schwartz MZ, Richardson CJ, Rassin DK, Gourley WK, Srivastava SK et al. Hexosaminidase: a marker for intestinal gangrene in necrotizing enterocolitis. J Pediatr Surg 1983; 18: 449–452.

    Article  CAS  Google Scholar 

  33. Shattuck KE, Richardson CJ, Rassin DK, Lobe TE . Evaluation of hexosaminidase activity as a potential biochemical marker in serum for necrotizing enterocolitis. J Pediatr Gastroenterol Nutr 1987; 6: 234–237.

    Article  CAS  Google Scholar 

  34. Ng PC, Ang IL, Chiu RW, Li K, Lam HS, Wong RP et al. Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants. J Clin Invest 2010; 120: 2989–3000.

    Article  CAS  Google Scholar 

  35. Wirbelauer J, Thomas W, Rieger L, Speer CP . Intrauterine growth retardation in preterm infants &lt;/=32 weeks of gestation is associated with low white blood cell counts. Am J Perinatol 2010; 27: 819–824.

    Article  Google Scholar 

  36. Lee JS, Sperry JL, Ochoa JB, Barclay D, Namas R, Vodovotz Y et al. Persistence of elevated plasma CXCL8 concentrations following red blood cell transfusion in a trauma cohort. Shock 2012; 37: 373–377.

    Article  CAS  Google Scholar 

  37. Raabe BM, Artwohl JE, Purcell JE, Lovaglio J, Fortman JD . Effects of weekly blood collection in C57BL/6 mice. J Am Assoc Lab Anim Sci 2011; 50: 680–685.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Shiou SR, Yu Y, Chen S, Ciancio MJ, Petrof EO, Sun J et al. Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis. J Biol Chem 2011; 286: 12123–12132.

    Article  CAS  Google Scholar 

  39. Guillen U, Cummings JJ, Bell EF, Hosono S, Frantz AR, Maier RF et al. International survey of transfusion practices for extremely premature infants. Semin Perinatol 2012; 36: 244–247.

    Article  Google Scholar 

  40. Rosebraugh MR, Widness JA, Nalbant D, Veng-Pedersen P . A mathematical modeling approach to quantify the role of phlebotomy losses and need for transfusions in neonatal anemia. Transfusion 2013; 53: 1353–1360.

    Article  Google Scholar 

  41. Clarke C, Baghdadi H, Howie AF, Mason JI, Walker SW, Beckett GJ . Selenium supplementation attenuates procollagen-1 and interleukin-8 production in fat-loaded human C3A hepatoblastoma cells treated with TGFbeta1. Biochim Biophys Acta 2010; 1800: 611–618.

    Article  CAS  Google Scholar 

  42. Savidge TC, Newman PG, Pan WH, Weng MQ, Shi HN, McCormick BA et al. Lipopolysaccharide-induced human enterocyte tolerance to cytokine-mediated interleukin-8 production may occur independently of TLR-4/MD-2 signaling. Pediatr Res 2006; 59: 89–95.

    Article  CAS  Google Scholar 

  43. Namachivayam K, Blanco CL, MohanKumar K, Jagadeeswaran R, Vasquez M, McGill-Vargas L et al. Smad7 inhibits autocrine expression of TGF-beta2 in intestinal epithelial cells in baboon necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2013; 304: G167–G180.

    Article  CAS  Google Scholar 

  44. Maheshwari G, Wiley HS, Lauffenburger DA . Autocrine epidermal growth factor signaling stimulates directionally persistent mammary epithelial cell migration. J Cell Biol 2001; 155: 1123–1128.

    Article  CAS  Google Scholar 

  45. Steel CD, Stephens AL, Hahto SM, Singletary SJ, Ciavarra RP . Comparison of the lateral tail vein and the retro-orbital venous sinus as routes of intravenous drug delivery in a transgenic mouse model. Lab Anim 2008; 37: 26–32.

    Article  Google Scholar 

  46. Maheshwari A, Corbin LL, Schelonka RL . Neonatal necrotizing enterocolitis. Res Rep Neonatol 2011; 1: 39–53.

    Google Scholar 

  47. Dorling J, Kempley S, Leaf A . Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonatal Ed 2005; 90: F359–F363.

    Article  CAS  Google Scholar 

  48. Andrews WW, Goldenberg RL, Faye-Petersen O, Cliver S, Goepfert AR, Hauth JC . The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol 2006; 195: 803–808.

    Article  CAS  Google Scholar 

  49. Chan KY, Leung FW, Lam HS, Tam YH, To KF, Cheung HM et al. Immunoregulatory protein profiles of necrotizing enterocolitis versus spontaneous intestinal perforation in preterm infants. PLoS One 2012; 7: e36977.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by an NIH award R01HD059142 (to AM).

Author information

Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA,

    J Remon & A Maheshwari

  2. Department of Pediatrics, Center for Neonatal and Pediatric Gastrointestinal Disease, University of Illinois at Chicago, Chicago, IL, USA,

    J Remon, R R Kaul & A Maheshwari

  3. Department of Pediatrics, Division of Neonatology, Loyola University Stritch School of Medicine, Maywood, IL, USA

    R Kampanatkosol & J K Muraskas

  4. Intermountain Healthcare Women and Newborns Clinical Program, Ogden, UT, USA

    R D Christensen

  5. McKay-Dee Hospital Center, Ogden, UT, USA

    R D Christensen

  6. Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA,

    A Maheshwari

Authors
  1. J Remon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Kampanatkosol
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R R Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J K Muraskas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R D Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Maheshwari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Maheshwari.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Remon, J., Kampanatkosol, R., Kaul, R. et al. Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance. J Perinatol 34, 549–554 (2014). https://doi.org/10.1038/jp.2014.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2014.52

This article is cited by

Search

Advanced search

Quick links