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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
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: Suggested Citation