A Pilot Study Identifying Brain-Targeting Adaptive Immunity in Pediatric Extracorporeal Membrane Oxygenation Patients with Acquired Brain Injury

Sterling B. Ortega, Poornima Pandiyan, Jana Windsor, Vanessa O. Torres, Uma M. Selvaraj, Amy Lee, Michael Morriss, Fenghua Tian, Lakshmi Raman, Ann M. Stowe

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Objectives: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury. Design: A single center prospective observational study. Setting: Pediatric and cardiac ICUs at a single tertiary care, academic center. Patients: Twenty pediatric extracorporeal membrane oxygenation patients (0-14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients Interventions: None. Measurements and Main Results: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10-23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation. Conclusions: We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS.

Original languageEnglish
Pages (from-to)e206-e213
JournalCritical Care Medicine
Volume47
Issue number3
DOIs
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
Drs. Tian and Raman were supported, in part by, American Heart Association (AHA) Beginning-Grant-in Aid (15BGIA25860045). Drs. Pandiyan and Raman were funded by Extracorporeal Life Support Organization research grant and UT Southwestern Center for Translational Medicine award. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. Dr. Stowe was supported from the AHA (14SDG 18410020), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS088555), Dr. Ortega (14POST20480373) and Ms. Selvaraj (17PRE33660147) from the AHA.

Funding Information:
1Departments of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX. 2Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX. 3Children's Health, Dallas, TX. 4Department of Bioengineering, UT Arlington, Arlington, TX. 5Department of Neurology, University of Kentucky, Lexington, KY. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drs. Ortega, Pandiyan, Raman, and Stowe contributed equally. Drs. Ortega and Pandiyan designed, performed, and analyzed the immunology-based assays and co-wrote the article. Dr. Pandiyan performed and analyzed the immunology-based assays as well as recruited patients and co-wrote the article. Ms. Windsor and Dr. Lee recruited patients and Ms. Windsor, Ms. Torres, Ms. Selvaraj, and Dr. Stowe processed samples. Dr. Tian quantified autoregulation disruption based on wavelength transform coherence. Dr. Morriss scored all neuroimaging. Drs. Raman and Stowe designed and supervised the study and co-wrote the article. All authors read, edited, and approved of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Tian and Raman were supported, in part by, American Heart Association (AHA) Beginning-Grant-in Aid (15BGIA25860045). Drs. Pandi-yan and Raman were funded by Extracorporeal Life Support Organization research grant and UT Southwestern Center for Translational Medicine award. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. Dr. Stowe was supported from the AHA (14SDG18410020), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS088555), Dr. Ortega (14POST20480373) and Ms. Selvaraj (17PRE33660147) from the AHA. Drs. Ortega’s, Pandiyan’s, Windsor’s, and Stowe’s institutions received funding from Extracorporeal Life Support Organization and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001105. Drs. Ortega, Pandiyan, Windsor, Torres, Raman, and Stowe received support for article research from the NIH. Dr. Tian’s institution received funding from the American Heart Association, and he disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Ann M. Stowe, PhD, Department of Neurology, University of Kentucky College of Medicine, 741 S. Limestone St., BBSRB 363, Lexington, KY, 40536. E-mail: Ann.Stowe@uky.edu Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Publisher Copyright:
Copyright © 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Keywords

  • B cells
  • autoreactivity
  • cerebral autoregulation
  • cytotoxic T cells
  • extracorporeal membrane oxygenation
  • helper T cells

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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