Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza

Frontiers in Immunology

Immunology

Georg Hahn¹  Barry Markovitz²  Neethi P. Pinto³  Tanya Novak⁴  Adrienne G. Randolph⁵  Simone A. Thair⁶  Margaret M. Newhams⁷  Jeremy Chase Crawford⁸  Christoph Lange⁹  Stephen C. Kurachek^1,10  Patrick McQuillen^1,11  Adam J. Schwarz^1,12  Neal J. Thomas^1,13  Peter M. Mourani^1,14  Kate G. Ackerman^1,15  Laura L. Loftis^1,16  Keiko M. Tarquinio^1,17  Mark W. Hall^1,18  Bria M. Coates^1,19  Natalie Z. Cvijanovich^2,20  Janet Chou^2,21  Steven L. Shein^2,22  Paul G. Thomas^2,23  Scott L. Weiss^2,24  Sidharth Mahapatra^2,25  David W. Tellez^2,26  Renee Higgerson^2,27  Rainer G. Gedeit^2,28  Ronald C. Sanders^2,29 

[1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States;Department of Anesthesiology Critical Care Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States;Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States;Department of Anaesthesia, Harvard Medical School, Boston, MA, United States;National Institute of Allergy and Infectious Diseases (NIAID), Centers of Excellence for Influenza Research and Response (CEIRR), Center for Influenza Disease and Emergence Response (CIDER), Athens, GA, United States;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States;Department of Anaesthesia, Harvard Medical School, Boston, MA, United States;National Institute of Allergy and Infectious Diseases (NIAID), Centers of Excellence for Influenza Research and Response (CEIRR), Center for Influenza Disease and Emergence Response (CIDER), Athens, GA, United States;Department of Pediatrics, Harvard Medical School, Boston, MA, United States;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States;Division of Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States;National Institute of Allergy and Infectious Diseases (NIAID), Centers of Excellence for Influenza Research and Response (CEIRR), Center for Influenza Disease and Emergence Response (CIDER), Athens, GA, United States;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States;National Institute of Allergy and Infectious Diseases (NIAID), Centers of Excellence for Influenza Research and Response (CEIRR), St. Jude Children's Research Hospital, Memphis, TN, United States;Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, United States;Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA, United States;Department of Critical Care, Children’s Specialty Center, Children’s Minnesota, Minneapolis, MN, United States;Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA, United States;Department of Pediatrics, Children’s Hospital of Orange County, Orange, CA, United States;Department of Pediatrics, Penn State Health Children’s Hospital, Penn State University College of Medicine, Hershey, PA, United States;Department of Pediatrics, Section of Critical Care Medicine, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, AR, United States;Department of Pediatrics, University of Rochester/UR Medicine Golisano Children’s Hospital, Rochester, NY, United States;Division of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States;Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, United States;Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States;Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States;Division of Critical Care Medicine, UCSF Benioff Children’s Hospital, Oakland, CA, United States;Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States;Department of Pediatrics, Harvard Medical School, Boston, MA, United States;Division of Pediatric Critical Care Medicine, University Hospitals Rainbow Babies and Children’s Hospital, Cleveland, OH, United States;National Institute of Allergy and Infectious Diseases (NIAID), Centers of Excellence for Influenza Research and Response (CEIRR), St. Jude Children's Research Hospital, Memphis, TN, United States;Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, United States;Nemours Children’s Hospital Delaware, Critical Care Medicine, Wilmington, DE, United States;Pediatric Critical Care Medicine, Children’s Hospital & Medical Center Omaha, University of Nebraska Medical Center, Omaha, NE, United States;Pediatric Critical Care Medicine, Phoenix Children’s Hospital, Phoenix, AZ, United States;Pediatric Critical Care Medicine, St. David’s Children’s Hospital, Austin, TX, United States;Pediatric Critical Care, Milwaukee Hospital-Children’s Wisconsin, Milwaukee, WI, United States;Section of Pediatric Critical Care, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, AR, United States;

关键词: influenza;    sepsis;    organ failure;    pediatric intensive care;    neutrophil degranulation;    MODS;    neutrophil transcripts;    critical care;   

DOI  :  10.3389/fimmu.2023.1220028

 received in 2023-05-09, accepted in 2023-06-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundInfluenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.MethodsWe measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05).ResultsComparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.ConclusionThus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.

【 授权许可】

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Copyright © 2023 Novak, Crawford, Hahn, Hall, Thair, Newhams, Chou, Mourani, Tarquinio, Markovitz, Loftis, Weiss, Higgerson, Schwarz, Pinto, Thomas, Gedeit, Sanders, Mahapatra, Coates, Cvijanovich, Ackerman, Tellez, McQuillen, Kurachek, Shein, Lange, Thomas and Randolph