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Circulating endothelial signatures correlate with worse outcomes in COVID-19, respiratory failure and ARDS
Ana C Costa Monteiro1, Harry Pickering2, Aartik Sarma3
1University of California School of Medicine- Los Angeles, Los Angeles, CA, USA. Acostamonteiro@mednet.ucla.edu.
Insights
Elevated endothelial cell signatures (ECS) in circulation correlate with worse outcomes in respiratory failure patients. This transcriptomic approach offers a non-invasive method to evaluate endothelial damage in ARDS and COVID-19.
Area of Science:
- Pulmonary Medicine
- Genomics
- Critical Care Medicine
Background:
- Elevated circulating endothelial cells (CECs) are linked to poor outcomes in ARDS and COVID-19.
- A consensus proteomic phenotype for CECs is lacking.
- This study explores a transcriptomic approach to identify endothelial cells in circulation.
Purpose of the Study:
- To determine if elevated endothelial cell signatures (ECS) in circulation correlate with worse respiratory outcomes.
- To validate a transcriptomic deconvolution method for quantifying ECS.
- To assess the association between ECS and mortality/respiratory failure severity.
Main Methods:
- Unsupervised bulk-transcriptome deconvolution was used to quantify ECS percentage.
- Two cohorts were analyzed: pediatric invasive mechanical ventilation (CAF-PINT) and adult COVID-19 (IMPACC).
- Primary outcome was 28-day mortality; secondary outcomes included respiratory trajectories.
Main Results:
- Higher day 0 ECS% was observed in non-survivors versus survivors in both pediatric and adult COVID-19 cohorts.
- Each 1% increase in baseline ECS% significantly associated with mortality (aOR 1.36).
- Increased baseline ECS% correlated with worse respiratory trajectories, including fatal outcomes.
Conclusions:
- Quantifying ECS via deconvolution supports a transcriptomic approach for non-invasive evaluation of endothelial damage.
- This method aids in understanding the link between endothelial damage and ARDS.
- Utilizes novel deconvolution of circulating transcriptomic data for mechanistic insights.
Background:
Elevated circulating endothelial cells (CECs), released from monolayers after insult, have been implicated in worse outcomes in ARDS and COVID-19, however there is no consensus proteomic phenotype that define CECs. We queried whether a transcriptomic approach would alternatively support the presence of endothelial cells in circulation and correlate with worsening respiratory failure.
Methods:
To test whether elevated endothelial cell signatures (ECS) in circulation plays a role in worse respiratory outcomes, we used unsupervised bulk-transcriptome deconvolution to quantify ECS% in two cohorts. Our pilot analysis included pediatric patients requiring invasive mechanical ventilation (CAF-PINT, NCT01892969). Our validation cohort included adult hospitalized patients with COVID-19 (IMPACC, NCT04378777), testing the association of ECS% to outcomes in patients at risk of acute respiratory failure/ARDS. Primary outcome was 28-day mortality.
Results:
In CAF-PINT, day 0 ECS% was higher in non-survivors compared to survivors of respiratory failure (2.8%, IQR 2.4-3.4% versus 2.6%, IQR 2.2-3.0% n = 244, p < 0.05, Wilcoxon rank-sum). In IMPACC, baseline ECS% (< 72 h of hospitalization) was higher in COVID-19 non-survivors versus survivors (2.9%, IQR 2.6-3.4%, versus 2.7%, IQR 2.3-3.1%, n = 932, p < 0.001, Wilcoxon rank-sum). Each 1% increase in baseline ECS% was significantly associated with mortality (adjusted OR 1.36, CI 1.03-1.79) by multivariable logistic regression. Increased baseline ECS% was associated with worse respiratory trajectories (2.5%, IQR 2.2-2.8% for trajectory with no oxygen requirements, 2.9%, IQR 2.6-3.4% for the trajectory with fatal outcome by day 28, n = 932, p < 0.001, one-way ANOVA).
Conclusion:
Quantifying ECS by deconvolution supports a transcriptomics-driven approach towards the non-invasive evaluation of endothelial damage in respiratory outcomes. This is a first step towards elucidating mechanistic components linking endothelial damage to ARDS utilizing non-invasive, circulating transcriptomic data by leveraging a novel deconvolution approach.
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