Circulating endothelial signatures correlate with worse outcomes in COVID-19, respiratory failure and ARDS

IF 9.3 1区医学 Q1 CRITICAL CARE MEDICINE

Critical Care Pub Date : 2025-10-14 DOI:10.1186/s13054-025-05596-0

Ana C. Costa Monteiro, Harry Pickering, Aartik Sarma, Clove S. Taylor, Meagan M. Jenkins, Fei-Man Hsu, Brian Nadel, Ofer Levy, Lindsey R. Baden, Esther Melamed, Lauren I. R. Ehrlich, Grace A. McComsey, Rafick P. Sekaly, Charles B. Cairns, Elias K. Haddad, Albert C. Shaw, David A. Hafler, Ruth R. Montgomery, David B. Corry, Farrah Kheradmand, Mark A. Atkinson, Scott C. Brakenridge, Nelson I. Agudelo Higuita, Jordan P. Metcalf, Catherine L. Hough, William B. Messer, Bali Pulendran, Kari C. Nadeau, Mark M. Davis, Linda N. Geng, Ana Fernandez-Sesma, Viviana Simon, Florian Krammer, Monica Kraft, Chris Bime, Carolyn S. Calfee, David J. Erle, Steve Bosinger, Walter Eckalbar, Holden Maecker, Adeeb Rahman, Leying Guan, Bjoern Peters, Steven H. Kleinstein, Alison D. Augustine, Joann Diray-Arce, Patrice M. Becker, Nadine Rouphael, Michael Agus, Hrishikesh Kulkarni, Joanna M. Schaenmann, Ramin Salehi-Rad, Michael A. Matthay, Elaine F. Reed, Anil Sapru

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引用次数: 0

Abstract

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. 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. 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). 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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循环内皮特征与COVID-19、呼吸衰竭和ARDS的预后较差相关

损伤后从单层释放的循环内皮细胞（CECs）升高与ARDS和COVID-19的预后较差有关，但对于CECs的蛋白质组学表型定义尚无共识。我们询问转录组学方法是否支持循环中内皮细胞的存在并与呼吸衰竭恶化相关。为了测试循环中内皮细胞特征（ECS）升高是否在更糟糕的呼吸结果中起作用，我们在两个队列中使用无监督的大体积转录组反褶积来量化ECS%。我们的试点分析包括需要有创机械通气的儿科患者（caft - pint, NCT01892969）。我们的验证队列包括COVID-19住院成人患者（IMPACC, NCT04378777），测试ECS%与急性呼吸衰竭/ARDS风险患者结局的关系。主要终点为28天死亡率。在caft - pint中，非存活患者的第0天ECS%高于呼吸衰竭存活患者（2.8%,IQR 2.4-3.4% vs 2.6%, IQR 2.2-3.0% n = 244, p < 0.05， Wilcoxon秩和）。在IMPACC中，COVID-19非幸存者的基线ECS% （< 72 h住院）高于幸存者（2.9%,IQR 2.6-3.4%，对2.7%,IQR 2.3-3.1%, n = 932, p < 0.001， Wilcoxon秩和）。多变量logistic回归显示，基线ECS%每增加1%与死亡率显著相关（校正OR 1.36, CI 1.03-1.79）。增加的基线ECS%与较差的呼吸轨迹相关（2.5%，无氧需求轨迹IQR 2.2-2.8%, 2.9%，有致命结果的轨迹IQR 2.6-3.4%, n = 932, p < 0.001，单因素方差分析）。通过反褶积量化ECS支持转录组学驱动的方法，用于呼吸结果中内皮损伤的无创评估。这是利用一种新的反褶积方法，利用无创循环转录组数据阐明内皮损伤与ARDS相关的机制成分的第一步。

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来源期刊

Critical Care 医学-危重病医学

CiteScore

20.60

自引率

3.30%

发文量

348

审稿时长

1.5 months

期刊介绍： Critical Care is an esteemed international medical journal that undergoes a rigorous peer-review process to maintain its high quality standards. Its primary objective is to enhance the healthcare services offered to critically ill patients. To achieve this, the journal focuses on gathering, exchanging, disseminating, and endorsing evidence-based information that is highly relevant to intensivists. By doing so, Critical Care seeks to provide a thorough and inclusive examination of the intensive care field.