Tanya Novak1, Mark W Hall2, Douglas R McDonald3, Margaret M Newhams4, Anushay J Mistry4, Angela Panoskaltsis-Mortari5, Peter M Mourani6, Laura L Loftis7, Scott L Weiss8, Keiko M Tarquinio9, Barry Markovitz10, Mary E Hartman11, Adam Schwarz12, Wolfgang G Junger13, Adrienne G Randolph14. 1. 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. 2. Nationwide Children's Hospital, Division of Critical Care Medicine, Department of Pediatrics, Columbus, Ohio. 3. Boston Children's Hospital, Division of Immunology and Harvard Medical School Department of Pediatrics, Boston, Mass. 4. Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass. 5. Cytokine Reference Laboratory, Department of Pediatrics, University of Minnesota, Minneapolis, Minn. 6. Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colo. 7. Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Houston, Tex. 8. Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pa. 9. Division of Pediatric Critical Care Medicine, Children's Healthcare of Atlanta at Egleston, Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga. 10. Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, Calif. 11. Department of Pediatrics, St Louis Children's Hospital, St Louis, Mo. 12. Department of Pediatrics, Children's Hospital of Orange County, Orange, Calif. 13. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. 14. 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.
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.
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 influenzacritical 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.
Authors: Mohammed Alsharifi; Matthias Regner; Robert Blanden; Mario Lobigs; Eva Lee; Aulikki Koskinen; Arno Müllbacher Journal: J Immunol Date: 2006-09-01 Impact factor: 5.422
Authors: Mark W Hall; Nina L Knatz; Carol Vetterly; Steven Tomarello; Mark D Wewers; Hans Dieter Volk; Joseph A Carcillo Journal: Intensive Care Med Date: 2010-12-10 Impact factor: 17.440
Authors: Mark W Hall; Susan M Geyer; Chao-Yu Guo; Angela Panoskaltsis-Mortari; Philippe Jouvet; Jill Ferdinands; David K Shay; Jyotsna Nateri; Kristin Greathouse; Ryan Sullivan; Tram Tran; Shannon Keisling; Adrienne G Randolph Journal: Crit Care Med Date: 2013-01 Impact factor: 7.598
Authors: Liesbeth Huys; Filip Van Hauwermeiren; Lien Dejager; Eline Dejonckheere; Stefan Lienenklaus; Siegfried Weiss; Georges Leclercq; Claude Libert Journal: J Exp Med Date: 2009-08-17 Impact factor: 14.307