RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness.,Journal of Allergy and Clinical Immunology

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RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-02-06 , DOI: 10.1016/j.jaci.2020.01.040
Tanya Novak ₁ , Mark W Hall ₂ , Douglas R McDonald ₃ , Margaret M Newhams ₄ , Anushay J Mistry ₄ , Angela Panoskaltsis-Mortari ₅ , Peter M Mourani ₆ , Laura L Loftis ₇ , Scott L Weiss ₈ , Keiko M Tarquinio ₉ , Barry Markovitz ₁₀ , Mary E Hartman ₁₁ , Adam Schwarz ₁₂ , Wolfgang G Junger ₁₃ , Adrienne G Randolph ₁₄ ,

Affiliation

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.
Nationwide Children's Hospital, Division of Critical Care Medicine, Department of Pediatrics, Columbus, Ohio.
Boston Children's Hospital, Division of Immunology and Harvard Medical School Department of Pediatrics, Boston, Mass.
Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass.
Cytokine Reference Laboratory, Department of Pediatrics, University of Minnesota, Minneapolis, Minn.
Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colo.
Section of Critical Care Medicine, Department of Pediatrics, Texas Children's Hospital, Houston, Tex.
Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pa.
Division of Pediatric Critical Care Medicine, Children's Healthcare of Atlanta at Egleston, Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga.
Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, Calif.
Department of Pediatrics, St Louis Children's Hospital, St Louis, Mo.
Department of Pediatrics, Children's Hospital of Orange County, Orange, Calif.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.
Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston.

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.

中文翻译：

RIG-I 和 TLR4 反应以及儿科流感相关危重疾病的不良后果。

背景

离体LPS 刺激后全血中 TNF-α 的产生减少表明 Toll 样受体 (TLR)4 途径受到抑制。这与小儿流感危重疾病死亡率的增加有关。这些患者的抗病毒免疫信号通路是否也受到抑制尚不清楚。

目标

我们试图评估 TLR4 和抗病毒视黄酸诱导基因 I (RIG-I) 通路的抑制与严重流感感染儿童的临床结果。

方法

在这项针对已确诊流感感染的儿童的 24 中心前瞻性观察队列研究中，在进入重症监护病房 72 小时内采集了血液。使用病毒配体聚肌苷-聚胞苷酸-低分子量/LyoVec 和 LPS 对匹配对照进行离体全血刺激，以评估 IFN-α 和 TNF-α 产生能力（分别为 RIG-I 和 TLR4 途径）。

结果

IFN-α 或 TNF-α 产生能力的抑制与机械通气和住院时间延长以及器官功能障碍增加相关。 RIG-I 和 TLR4 通路均受到抑制的儿童（n = 103 名中的 33 名 [32%]）更有可能患有长期（≥7 天）多器官功能障碍综合征（30.3% vs 8.6%； P = .004）与单通路抑制或无通路抑制的患者相比，出现长期低氧性呼吸衰竭（39.4% vs 11.4%； P = .001）。