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Are elevated peripheral leukocytes markers of septic etiology in asphyxiated infants with neurological disability?

Journal of Perinatology volume 28, pages 85–86 (2008)Cite this article

Thank you for your interest in our paper titled ‘Elevated total peripheral leukocyte count may identify risk for neurologic disability in asphyxiated term neonates.’1 We agree with your comments that bacterial infection significantly augments hypoxic–ischemic neuronal injury. However, we did not find any documentation of bacterial infection in the first week of life in our cohort of infants who had poor neurologic outcome at 18 months of age. There was no documented maternal fever or clinical/histological chorioamnionitis in any of the mothers of the babies. Blood and CSF cultures obtained in the first 3 days of life came back negative or ‘No Growth.’ Only 6/9 infants had cranial ultrasounds, the results of which came back negative or within normal limits.

Because none of the neonates in the ‘poor outcome’ group had evidence of bacterial infection, we speculated that the observed leukocytosis and neutrophilia may be due to a hypoxia–ischemia-induced activation of the inflammatory cascade. One of the hallmark responses of ischemia is a pronounced inflammatory response, characterized by neutrophil recruitment into the ischemic zone.2 Hypoxia increases leukocyte production and the number of circulating neutrophils.3 In addition, hypoxia is observed to cause a dramatic decrease in neutrophil apoptosis, significantly prolonging neutrophil survival and exacerbating neutrophil-mediated tissue destruction.4 Specifically, cell injury or cell death due to hypoxia–ischemia can activate surrounding immune cells such as microglia and astrocytes5 leading to the synthesis and production of pro-inflammatory cytokines such as interleukin 1β, interleukin6 and tumor necrosis factor α (TNF-α).6 Cytokines increase vascular permeability7 and upregulate expression of intercellular adhesion molecules, mediators that induce migration of leukocytes and promote local inflammatory reactions.8 In addition, cytokines increase the affinity of neutrophil integrins to intercellular adhesion molecules8, 9 promoting trans-endothelial migration.7, 10, 11 Inflammation-induced cell injury occurs due to the ‘oxidation burst’ that involves neutrophil production of reactive and toxic metabolites such as hydrogen peroxide, superoxide anion and hypochlorous acid.12, 13 Thus, in addition to core tissue damage from a deficiency in oxygen or reduced blood flow, a penumbra of cell injury progresses from invasion of phagocytes and local production of free-radicals and toxic metabolites.

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References

  1. Morkos AA, Hopper AO, Deming DD, Yellon SM, Wycliffe N, Ashwal S et al. Elevated total peripheral leukocyte count may identify risk for neurologic disability in asphyxiated term neonates. J Perinatol 2007; 27: 365–370.

    Article  CAS  Google Scholar 

  2. Emerich DF, Dean RL, Bartus RT . The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? Exp Neurol 2002; 173: 168–181.

    Article  Google Scholar 

  3. Zyuz'kov GN, Dygai AM, Gol'dberg ED . Changes in granulocytic hemopoietic stem and their mechanisms during hypoxia of different genesis. Bull Exp Biol Med 2005; 139: 279–282.

    Article  CAS  Google Scholar 

  4. Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, Haslett C et al. Hypoxia prolongs neutrophil survival in vitro. FEBS Lett. 1995; 372: 233–237.

    Article  CAS  Google Scholar 

  5. Mander PK, Jekabsone A, Brown GC . Microglia proliferation is regulated by hydrogen peroxide from NADPH oxidase. J Immunol 2006; 176: 1046–1052.

    Article  CAS  Google Scholar 

  6. Sun Y, Calvert JW, Zhang JH . Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration. Stroke 2005; 36: 1672–1678.

    Article  CAS  Google Scholar 

  7. Panes J, Perry M, Granger DN . Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention. Br J Pharmacol 1999; 126: 537–550.

    Article  CAS  Google Scholar 

  8. Weston RM, Jones NM, Jarrott B, Callaway JK . Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J Cereb Blood Flow Metab 2006; 27: 100–114.

    Article  Google Scholar 

  9. Ivanov KP, Mel'nikova NN . The role of leukocytes in microcirculation dynamics in the norm and pathology. Vestn Ross Akad Med Nauk 2004; 4: 3–13.

    Google Scholar 

  10. Kim MB, Sarelius IH . Role of shear forces and adhesion molecule distribution on P-selectin-mediated leukocyte rolling in postcapillary venules. Am J Physiol Heart Circ Physiol 2004; 287: H2705–H2711.

    Article  CAS  Google Scholar 

  11. Kataoka H, Kim SW, Plesnila N . Leukocyte-endothelium interactions during permanent focal cerebral ischemia in mice. J Cereb Blood Flow Metab 2004; 24: 668–676.

    Article  Google Scholar 

  12. Hudome S, Palmer C, Roberts RL, Mauger D, Housman C, Towfighi J . The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res 1997; 41: 607–616.

    Article  CAS  Google Scholar 

  13. Dinkel K, Dhabhar FS, Sapolsky RM . Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures. Proc Natl Acad Sci USA 2004; 101: 331–336.

    Article  CAS  Google Scholar 

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  1. Loma Linda University School of Medicine, Loma Linda, CA, USA

    D M Angeles, S Ashwal, D Deming, S Yellon, A Hopper & R Peverini

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  1. D M Angeles
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  2. S Ashwal
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  3. D Deming
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  4. S Yellon
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  5. A Hopper
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  6. R Peverini
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Correspondence to D M Angeles.

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Angeles, D., Ashwal, S., Deming, D. et al. Are elevated peripheral leukocytes markers of septic etiology in asphyxiated infants with neurological disability?. J Perinatol 28, 85–86 (2008). https://doi.org/10.1038/sj.jp.7211856

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