lancet-header

Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.

Tracheal Aspirate and Plasma Proteomics Reveals the Local and Systemic Host Immune Response to Severe Pediatric Lower Respiratory Viral Infections

34 Pages Posted: 26 Jun 2024

See all articles by Emily C. Lydon

Emily C. Lydon

University of California, San Francisco (UCSF)

Christina M. Osborne

University of Pennsylvania - Children's Hospital of Philadelphia

Brandie D. Wagner

Department of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health

Lilliam Ambroggio

Children's Hospital Colorado

J. Kirk Harris

Department of Pediatrics, Section of Pulmonary Medicine, University of Colorado School of Medicine

Ron W. Reeder

University of Utah

Todd C. Carpenter

Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado

Aline B. Maddux

Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado

Matthew K. Leroue

Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado

Nadir Yehya

University of Pennsylvania - Children's Hospital of Philadelphia

Joseph L. DeRisi

University of California, San Francisco (UCSF) - UCSF Medical Center

Mark W. Hall

Nationwide Children’s Hospital

Athena F. Zuppa

University of Pennsylvania - Children's Hospital of Philadelphia

Joseph Carcillo

University of Pittsburgh

Kathleen L. Meert

affiliation not provided to SSRN

Anil Sapru

University of California, Los Angeles (UCLA) - Department of Pediatrics

Murray M. Pollack

Department of Pediatrics, Children’s National Medical Center and George Washington School of Medicine and Health Services

Patrick S. McQuillen

University of California, San Francisco (UCSF)

Daniel A. Notterman

Princeton University

Charles Langelier

University of California, San Francisco (UCSF) - Division of Infectious Diseases

Peter M. Mourani

Children's Hospital Colorado

More...

Abstract

Background: Viral lower respiratory tract infections (vLRTI) are a leading cause of child mortality. Improved understanding of host immune responses to severe vLRTI could reveal insights into pathophysiology, lead to novel diagnostic tests, and inform personalized treatment. While transcriptional profiling has advanced understanding of vLRTI in critically ill children, no studies have yet employed proteomics to simultaneously characterize the lower airway and systemic host response. In this study, we sought to deeply characterize proteomic responses to severe pediatric vLRTI. 

Methods: We assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 patients with acute respiratory failure using SomaScan®. We performed differential expression and pathway analyses between vLRTI (n=40) and non-infectious respiratory failure controls (n=22), developed a classifier using LASSO regression, and comparatively analyzed TA and plasma samples. Subanalyses within the vLRTI group investigated the impact of viral load and bacterial coinfection on the proteome.

Findings: The lower respiratory signature of vLRTI was characterized by 200 differentially expressed proteins (adjusted p-value<0.05). Pathway analysis demonstrated upregulation of interferon, NK cell, and cytotoxic T cell responses and downregulation of inflammation-modulating proteins MIP-5, NAP-2 and FABP. A nine-protein TA classifier achieved an AUC of 0.96 (95% CI 0.90-1.00) for distinguishing vLRTI from noninfectious respiratory failure. The host response to vLRTI in plasma was more subtle with 56 differentially expressed proteins. Correlation between TA and plasma was generally weak, although the interferon-stimulated protein ISG15 was elevated in both compartments. Bacterial coinfection was characterized by increased TNF-stimulated protein TSG-6, C-reactive protein, and interferon signaling compared to viral infection alone. Viral load correlated positively with interferon expression and negatively with neutrophil activation protein expression.

Interpretation: We characterized the lower airway and systemic proteomic host response of severe pediatric vLRTI and identified protein biomarkers with diagnostic potential.

Funding: NIH NHLBI; Chan Zuckerberg Biohub.

Declaration of Interest: The authors declare no conflicts of interest.

Ethical Approval: IRB approval was granted for TA sample collection prior to consent, as daily endotracheal suctioning is standard-of-care. Specimens of children for whom consent was not obtained were destroyed. The study was approved by the University of Utah central IRB #00088656.

Keywords: pneumonia, viral pneumonia, lower respiratory tract infection, LRTI, viral LRTI, viral, coinfection, bacterial superinfection, pediatrics, diagnostics, biomarker, host response, proteomics, SomaScan

Suggested Citation

Lydon, Emily C. and Osborne, Christina M. and Wagner, Brandie D. and Ambroggio, Lilliam and Harris, J. Kirk and Reeder, Ron W. and Carpenter, Todd C. and Maddux, Aline B. and Leroue, Matthew K. and Yehya, Nadir and DeRisi, Joseph L. and Hall, Mark W. and Zuppa, Athena F. and Carcillo, Joseph and Meert, Kathleen L. and Sapru, Anil and Pollack, Murray M. and McQuillen, Patrick S. and Notterman, Daniel A. and Langelier, Charles and Mourani, Peter M., Tracheal Aspirate and Plasma Proteomics Reveals the Local and Systemic Host Immune Response to Severe Pediatric Lower Respiratory Viral Infections. Available at SSRN: https://ssrn.com/abstract=4875988 or http://dx.doi.org/10.2139/ssrn.4875988

Emily C. Lydon (Contact Author)

University of California, San Francisco (UCSF) ( email )

Christina M. Osborne

University of Pennsylvania - Children's Hospital of Philadelphia ( email )

Brandie D. Wagner

Department of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health ( email )

Aurora, CO
United States

Lilliam Ambroggio

Children's Hospital Colorado ( email )

J. Kirk Harris

Department of Pediatrics, Section of Pulmonary Medicine, University of Colorado School of Medicine ( email )

Aurora, CO 80045
United States

Ron W. Reeder

University of Utah

1645 E. Campus Center
Salt Lake City, UT 84112
United States

Todd C. Carpenter

Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado ( email )

Aurora, CO 80045
United States

Aline B. Maddux

Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado ( email )

Aurora, CO 80045
United States

Matthew K. Leroue

Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children’s Hospital Colorado ( email )

Aurora, CO 80045
United States

Nadir Yehya

University of Pennsylvania - Children's Hospital of Philadelphia ( email )

Joseph L. DeRisi

University of California, San Francisco (UCSF) - UCSF Medical Center

505 Parnassus Ave
San Francisco, CA 94143
United States

Mark W. Hall

Nationwide Children’s Hospital ( email )

Columbus, OH
United States

Athena F. Zuppa

University of Pennsylvania - Children's Hospital of Philadelphia ( email )

Joseph Carcillo

University of Pittsburgh

135 N Bellefield Ave
Pittsburgh, PA 15260
United States

Kathleen L. Meert

affiliation not provided to SSRN ( email )

No Address Available

Anil Sapru

University of California, Los Angeles (UCLA) - Department of Pediatrics ( email )

Los Angeles, CA
United States

Murray M. Pollack

Department of Pediatrics, Children’s National Medical Center and George Washington School of Medicine and Health Services ( email )

3200m St NW
Washington, DC 20037
United States

Patrick S. McQuillen

University of California, San Francisco (UCSF) ( email )

Daniel A. Notterman

Princeton University

22 Chambers Street
Princeton, NJ 08544-0708
United States

Charles Langelier

University of California, San Francisco (UCSF) - Division of Infectious Diseases ( email )

San Francisco, CA
United States

Peter M. Mourani

Children's Hospital Colorado ( email )

Aurora, CO 80045
United States

Click here to go to TheLancet.com

Paper statistics

Downloads
37
Abstract Views
187
PlumX Metrics