Faculty Collaboration Database

RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness. J Allergy Clin Immunol 2020 Jun;145(6):1673-1680.e11

Date

02/09/2020

Pubmed ID

32035159

Pubmed Central ID

PMC7323584

DOI

10.1016/j.jaci.2020.01.040

Scopus ID

2-s2.0-85081281320 (requires institutional sign-in at Scopus site)   16 Citations

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.

Author List

Novak T, Hall MW, McDonald DR, Newhams MM, Mistry AJ, Panoskaltsis-Mortari A, Mourani PM, Loftis LL, Weiss SL, Tarquinio KM, Markovitz B, Hartman ME, Schwarz A, Junger WG, Randolph AG, PALISI Pediatric Intensive Care Influenza (PICFLU) Network Investigators

Author

Rainer G. Gedeit MD Associate Chief Medical Officer in the Children's Administration department at Children's Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Antiviral Agents
Child
Child, Preschool
Critical Illness
DEAD Box Protein 58
Female
Humans
Influenza, Human
Interferon-alpha
Male
Prospective Studies
Receptors, Immunologic
Signal Transduction
Toll-Like Receptor 4
Tumor Necrosis Factor-alpha