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.
Bibliographical noteFunding Information:
Financial support was provided by the National Institutes of Health (grant nos. R01AI084011 and R21HD095228 to A.G.R.; grant no. 5T32GM103702-05 to W.G.J. and T.N.; and grant no. 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.). Disclosure of potential conflict of interest: T. Novak reports grants from the National Institutes of Health (NIH) and Boston Children's Hospital during the conduct of the study. M. W. Hall reports grants from the NIH during the conduct of the study; personal fees from LaJolla Pharmaceuticals; and personal fees from Bristol Myers-Squibb outside the submitted work. A. Panoskaltsis-Mortari and P. M. Mourani report grants from the NIH during the conduct of the study. S. L. Weiss reports grants from the National Institute of General Medical Sciences outside the submitted work. W. G. Junger reports grants from the NIH during the conduct of the study. A. G. Randolph reports grants from the NIH during the conduct of the study, grants from Genentech Inc outside the submitted work, and personal fees from LaJolla Pharmaceuticals. The rest of the authors declare that they have no relevant conflicts of interest.
- Polyinosinic:polycytidylic acid
- Toll-like receptor 4
- critical care
- retinoic acid–inducible gene-I
PubMed: MeSH publication types
- Journal Article
- Multicenter Study
- Observational Study
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't