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Decreased Expression of Serum and Microvascular Vascular Endothelial Growth Factor Receptor-2 in Meningococcal Sepsis*

van der Flier, Michiel MD, PhD1,2; Baerveldt, Ewout M. MD3,4; Miedema, Annemieke MD5; Hartwig, Nico G. MD, PhD6; Hazelzet, Jan A. MD, PhD7; Emonts, Marieke MD, PhD6; de Groot, Ronald MD, PhD1,2; Prens, Errol P. MD, PhD3,4; van Vught, Adrianus J. MD, PhD5; Jansen, Nicolaas J. MD, PhD5

Pediatric Critical Care Medicine: September 2013 - Volume 14 - Issue 7 - p 682–685
doi: 10.1097/PCC.0b013e3182917ccb
Feature Articles

Objectives: To determine the skin microvessel expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels in children with meningococcal sepsis.

Design: Observational study.

Setting: Two tertiary academic children hospital PICUs.

Patients: Children with meningococcal sepsis.

Intervention: Skin biopsy and blood sample collection.

Measurements and Main Results: Determination of skin microvessel vascular endothelial growth factor receptor 2 expression in skin biopsies by immunohistochemistry and measurement of serum-soluble vascular endothelial growth factor receptor 2 by enzyme-linked immunosorbent assay. Percentage of vascular endothelial growth factor receptor 2-positive skin microvessels and the staining intensity were significantly lower in children with meningococcal sepsis (n = 10) compared to controls (7.6% ± 8.8% vs 44.6% ± 39.2%; p = 0.009 and 0.7% ± 0.7% vs 1.7% ± 1.1%; p = 0.033, respectively). In addition, circulating serum levels of soluble vascular endothelial growth factor receptor 2 were decreased in sepsis (8,148 ± 1,140 pg/mL vs 13,414 ± 2,692 pg/mL; p < 0.001). Serum-soluble vascular endothelial growth factor receptor 2 levels (n = 28) were inversely correlated with Pediatric Risk of Mortality III score (r = –0.43; p = 0.023) and more decreased in nonsurvivors compared to survivors (5,640 ± 1,940 pg/mL vs 7,378 ± 2,336 pg/mL; p = 0.037).

Conclusions: Microvascular expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels are decreased in children with sepsis. Serum-soluble vascular endothelial growth factor receptor 2 levels are inversely correlated with disease severity indicated by Pediatric Risk of Mortality III score and survival. Decreased vascular endothelial growth factor receptor 2 expression may hinder natural recovery from sepsis-associated microvascular injury and the effectiveness of therapeutic strategies targeting vascular endothelial growth factor-vascular endothelial growth factor receptor 2 signaling in sepsis patients.

1Department of Pediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands.

2The Nijmegen Institute for Infection, Inflammation, and Immunity, Radboud University Medical Centre, Nijmegen, The Netherlands.

3Department of Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands.

4Department of Dermatology, Erasmus Medical Centre, Rotterdam, The Netherlands.

5Pediatric Intensive Care Unit, University Medical Centre Utrecht, Utrecht, The Netherlands.

6Department of Pediatric Infectious Diseases and Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands.

7Pediatric Intensive Care Unit, Erasmus Medical Centre, Rotterdam, The Netherlands.

* See also p. 720.

Presented, in part, at the 26th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), Graz, Austria, May 13–17, 2008, P01-69.

Dr. van der Flier was financially supported by the European Society of Paediatric Infectious Diseases (ESPID) Small Grant Program. Dr. Emonts is a board member for ESPID and have received reimbursement of travel expenses only; is employed by Erasmus Medical Centre; and has grants pending for FP7. Dr. Hartwig lectured for GSK and Abbott, consulted for GSK, and received support for travel from GSK. Dr. de Groot received a grant from European Union, FP7 Program; and is employed by Radboud University Nijmegen Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: m.flier@cukz.umcn.nl

©2013The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies