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

Adolescent Antiviral Agents / therapeutic use Child Child, Preschool Critical Illness DEAD Box Protein 58 / metabolism Female Humans Influenza, Human / drug therapy Interferon-alpha / metabolism Male Prospective Studies Receptors, Immunologic / metabolism Signal Transduction / drug effects Toll-Like Receptor 4 / metabolism Tumor Necrosis Factor-alpha / metabolism
IFN-α LPS Polyinosinic:polycytidylic acid TNF-α Toll-like receptor 4 critical care influenza pediatric retinoic acid–inducible gene-I suppression

Journal

The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002

Informations de publication

Date de publication:
06 2020
Historique:
received: 20 09 2019
revised: 13 01 2020
accepted: 15 01 2020
pubmed: 9 2 2020
medline: 20 2 2021
entrez: 9 2 2020
Statut: ppublish

Résumé

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. 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. 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). 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.jaci.2020.01.040 PMID: 32035159 PMC: PMC7323584
pubmed: 32035159
pii: S0091-6749(20)30179-2
doi: 10.1016/j.jaci.2020.01.040
pmc: PMC7323584
mid: NIHMS1573421
pii:
doi:

Substances chimiques

Antiviral Agents 0
Interferon-alpha 0
Receptors, Immunologic 0
TLR4 protein, human 0
Toll-Like Receptor 4 0
Tumor Necrosis Factor-alpha 0
RIGI protein, human EC 3.6.1.-
DEAD Box Protein 58 EC 3.6.4.13

Types de publication

Journal Article Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1673-1680.e11

Subventions

Organisme : NIGMS NIH HHS
ID : T32 GM103702
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI084011
Pays : United States
Organisme : NICHD NIH HHS
ID : R21 HD095228
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM136429
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD098363
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI084011
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM116162
Pays : United States

Investigateurs

Ronald C Sanders (RC)
Olivia K Irby (OK)
Glenda Hefley (G)
David Tellez (D)
Katri Typpo (K)
Barry Markovitz (B)
Heidi Flori (H)
Natalie Cvijanovich (N)
Nick Anas (N)
Adam Schwarz (A)
Ofelia Vargas-Shiraishi (O)
Anil Sapru (A)
Patrick McQuillen (P)
Angela Czaja (A)
Peter Mourani (P)
Matthew Paden (M)
Keiko Tarquinio (K)
Cheryl L Stone (CL)
Juliane Bubeck Wardenburg (JB)
Neethi Pinto (N)
Vicki Montgomery (V)
Janice E Sullivan (JE)
Adrienne G Randolph (AG)
Anna A Agan (AA)
Stephanie Ash (S)
Anushay Mistry (A)
Margaret Newhams (M)
Stephen C Kurachek (SC)
Allan Doctor (A)
Mary Hartman (M)
Edward Truemper (E)
Sidharth Mahapatra (S)
Machelle Dawson (M)
Kate Ackerman (K)
L Eugene Daugherty (LE)
Ryan Nofziger (R)
Steve Shein (S)
Mark W Hall (MW)
Lisa Steele (L)
Lisa Hanson-Huber (L)
Neal J Thomas (NJ)
Debra Spear (D)
Julie Fitzgerald (J)
Scott Weiss (S)
Jenny L Bush (JL)
Kathryn Graham (K)
Renee Higgerson (R)
LeeAnn Christie (L)
Laura L Loftis (LL)
Nancy Jaimon (N)
Rainer Gedeit (R)
Kathy Murkowski (K)

Informations de copyright

Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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Auteurs

Tanya Novak (T)

Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston.

Mark W Hall (MW)

Nationwide Children's Hospital, Division of Critical Care Medicine, Department of Pediatrics, Columbus, Ohio.

Douglas R McDonald (DR)

Boston Children's Hospital, Division of Immunology and Harvard Medical School Department of Pediatrics, Boston, Mass.

Margaret M Newhams (MM)

Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass.

Anushay J Mistry (AJ)

Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass.

Angela Panoskaltsis-Mortari (A)

Cytokine Reference Laboratory, Department of Pediatrics, University of Minnesota, Minneapolis, Minn.

Peter M Mourani (PM)

Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colo.

Laura L Loftis (LL)

Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Houston, Tex.

Scott L Weiss (SL)

Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pa.

Keiko M Tarquinio (KM)

Division of Pediatric Critical Care Medicine, Children's Healthcare of Atlanta at Egleston, Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga.

Barry Markovitz (B)

Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, Calif.

Mary E Hartman (ME)

Department of Pediatrics, St Louis Children's Hospital, St Louis, Mo.

Adam Schwarz (A)

Department of Pediatrics, Children's Hospital of Orange County, Orange, Calif.

Wolfgang G Junger (WG)

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Adrienne G Randolph (AG)

Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston. Electronic address: adrienne.randolph@childrens.harvard.edu.

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