RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness

• Type of Material: Article
• Authors: Matthew Paden, Emory University; Keiko Tarquinio, Emory University; Tanya Novak, Children's Hospital Boston; Mark W Hall, Nationwide Children’s Hospital; Douglas R McDonald, Harvard Medical School; Margaret M Newhams, Children's Hospital Boston; Anushay J Mistry, Children's Hospital Boston; Angela Panoskaltsis-Mortari, University of Minnesota Twin Cities; Peter M Mourani, University of Colorado School of Medicine; Laura L Loftis, Texas Children's Hospital Houston; Scott L Weiss, The Children's Hospital of Philadelphia; Bary Markovitz, Children's Hospital Los Angeles; Mary E Hartman, St. Louis Children's Hospital; Adam Schwarz, CHOC Children‘s UC Irvine School of Medicine; Wofgang G Junger, Harvard Medical School; Adrienne G Randolph, Children's Hospital Boston
• Language: English
• Date: 2020-06-01
• Publisher: Emory University Libraries
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 American Academy of Allergy, Asthma & Immunology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaci.2020.01.040
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology
• Volume: 145
• Issue: 6
• Start Page: 1673
• End Page: 1680.e11
• Grant/Funding Information: Financial support provided by the National Institute of Health (R01AI084011 and R21HD095228 to A.G.R; 5T32GM103702-05 to W.G.J and T.N; R01HD098363 to W.G.J. and A.G.R) and The Anesthesia Trailblazer Award from The Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital (to T.N.).
• Keywords: Antiviral Agents; Adolescent; Critical Illness; critical care; DEAD Box Protein 58; influenza; Interferon-alpha; TNF-α; Toll-like receptor 4; Humans; Signal Transduction; Polyinosinic:polycytidylic acid; Child; LPS; Female; Influenza, Human; Toll-Like Receptor 4; Receptors, Immunologic; IFN-α; Male; Tumor Necrosis Factor-alpha; Child, Preschool; retinoic acid–inducible gene-I; pediatric; suppression; Prospective Studies

Abstract

Background: Decreased TNF-α production in whole blood after ex vivo LPS stimulation indicates suppression of the Toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether antiviral immune signaling pathways are also suppressed in these patients is unclear. Objectives: We sought to evaluate suppression of the TLR4 and the antiviral retinoic acid–inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection. Methods: In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand polyinosinic-polycytidylic acid-low-molecular-weight/LyoVec and LPS to evaluate IFN-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively). Results: Suppression of either IFN-α or TNF-α production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n = 33 of 103 [32%]) were more likely to have prolonged (≥7 days) multiple-organ dysfunction syndrome (30.3% vs 8.6%; P = .004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4%; P = .001) compared with those with single- or no pathway suppression. Conclusions: Suppression of both RIG-I and TLR4 signaling pathways, essential for respective antiviral and antibacterial responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial coinfection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring.