Scholarlink

Background <p>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.</p> Methods <p>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.</p> Results <p>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 &lt; 0.05, Wilcoxon rank-sum). In IMPACC, baseline ECS% (&lt; 72&#xa0;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 &lt; 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 &lt; 0.001, one-way ANOVA).</p> Conclusion <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月14日

查看全文
  • 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,
  • Patrice M. Becker,
  • Alison D. Augustine,
  • Steven M. Holland,
  • Lindsey B. Rosen,
  • Serena Lee,
  • Tatyana Vaysman,
  • Al Ozonoff,
  • Joann Diray-Arce,
  • Jing Chen,
  • Alvin Kho,
  • Carly E. Milliren,
  • Annmarie Hoch,
  • Ana C. Chang,
  • Kerry McEnaney,
  • Brenda Barton,
  • Claudia Lentucci,
  • Maimouna D. Murphy,
  • Mehmet Saluvan,
  • Tanzia Shaheen,
  • Shanshan Liu,
  • Caitlin Syphurs,
  • Marisa Albert,
  • Arash Nemati Hayati,
  • Robert Bryant,
  • James Abraham,
  • Sanya Thomas,
  • Mitchell Cooney,
  • Meagan Karoly,
  • Matthew C. Altman,
  • Naresh Doni Jayavelu,
  • Scott Presnell,
  • Bernard Kohr,
  • Tomasz Jancsyk,
  • Azlann Arnett,
  • Bjoern Peters,
  • James A. Overton,
  • Randi Vita,
  • Kerstin Westendorf,
  • James A. Overton,
  • Ofer Levy,
  • Hanno Steen,
  • Patrick van Zalm,
  • Benoit Fatou,
  • Kinga K. Smolen,
  • Arthur Viode,
  • Simon van Haren,
  • Meenakshi Jha,
  • David Stevenson,
  • Lindsey R. Baden,
  • Kevin Mendez,
  • Jessica Lasky-Su,
  • Alexandra Tong,
  • Rebecca Rooks,
  • Michael Desjardins,
  • Amy C. Sherman,
  • Stephen R. Walsh,
  • Xhoi Mitre,
  • Jessica Cauley,
  • Xiofang Li,
  • Bethany Evans,
  • Christina Montesano,
  • Jose Humberto Licona,
  • Jonathan Krauss,
  • Nicholas C. Issa,
  • Jun Bai Park Chang,
  • Natalie Izaguirre,
  • Scott R. Hutton,
  • Greg Michelotti,
  • Kari Wong,
  • Scott J. Tebbutt,
  • Casey P. Shannon,
  • Rafick-Pierre Sekaly,
  • Slim Fourati,
  • Grace A. McComsey,
  • Paul Harris,
  • Scott Sieg,
  • George Yendewa,
  • Mary Consolo,
  • Heather Tribout,
  • Susan Pereira Ribeiro,
  • Charles B. Cairns,
  • Elias K. Haddad,
  • Michele A. Kutzler,
  • Mariana Bernui,
  • Gina Cusimano,
  • Jennifer Connors,
  • Kyra Woloszczuk,
  • David Joyner,
  • Carolyn Edwards,
  • Edward Lee,
  • Edward Lin,
  • Nataliya Melnyk,
  • Debra L. Powell,
  • James N. Kim,
  • I. Michael Goonewardene,
  • Brent Simmons,
  • Cecilia M. Smith,
  • Mark Martens,
  • Brett Croen,
  • Nicholas C. Semenza,
  • Mathew R. Bell,
  • Sara Furukawa,
  • Renee McLin,
  • George P. Tegos,
  • Brandon Rogowski,
  • Nathan Mege,
  • Kristen Ulring,
  • Pam Schearer,
  • Judie Sheidy,
  • Crystal Nagle,
  • Vicki Seyfert-Margolis,
  • Nadine Rouphael,
  • Steven E. Bosinger,
  • Arun K. Boddapati,
  • Greg K. Tharp,
  • Sonia Wimalasena,
  • Kathryn L. Pellegrini,
  • Brandi Johnson,
  • Bernadine Panganiban,
  • Christopher Huerta,
  • Evan J. Anderson,
  • Hady Samaha,
  • Jonathan E. Sevransky,
  • Laurel Bristow,
  • Elizabeth Beagle,
  • David Cowan,
  • Sydney Hamilton,
  • Thomas Hodder,
  • Amer Bechnak,
  • Andrew Cheng,
  • Aneesh Mehta,
  • Caroline R. Ciric,
  • Christine Spainhour,
  • Erin Carter,
  • Erin M. Scherer,
  • Jacob Usher,
  • Kieffer Hellmeister,
  • Laila Hussaini,
  • Lauren Hewitt,
  • Nina Mcnair,
  • Ana Fernandez-Sesma,
  • Viviana Simon,
  • Florian Krammer,
  • Harm Van Bakel,
  • Seunghee Kim-Schulze,
  • Ana Silvia Gonzalez-Reiche,
  • Jingjing Qi,
  • Brian Lee,
  • Juan Manuel Carreño,
  • Gagandeep Singh,
  • Ariel Raskin,
  • Johnstone Tcheou,
  • Zain Khalil,
  • Adriana van de Guchte,
  • Keith Farrugia,
  • Zenab Khan,
  • Geoffrey Kelly,
  • Komal Srivastava,
  • Lily Q. Eaker,
  • Maria C. Bermúdez-González,
  • Lubbertus C. F. Mulder,
  • Katherine F. Beach,
  • Miti Saksena,
  • Deena Altman,
  • Erna Kojic,
  • Levy A. Sominsky,
  • Arman Azad,
  • Dominika Bielak,
  • Hisaaki Kawabata,
  • Temima Yellin,
  • Miriam Fried,
  • Leeba Sullivan,
  • Sara Morris,
  • Giulio Kleiner,
  • Daniel Stadlbauer,
  • Jayeeta Dutta,
  • Hui Xie,
  • Manishkumar Patel,
  • Kai Nie,
  • Adeeb Rahman,
  • William B. Messer,
  • Catherine L. Hough,
  • Sarah A. R. Siegel,
  • Peter E. Sullivan,
  • Zhengchun Lu,
  • Amanda E. Brunton,
  • Matthew Strand,
  • Zoe L. Lyski,
  • Felicity J. Coulter,
  • Courtney Micheleti,
  • Holden Maecker,
  • Bali Pulendran,
  • Kari C. Nadeau,
  • Yael Rosenberg-Hasson,
  • Michael Leipold,
  • Natalia Sigal,
  • Angela Rogers,
  • Andrea Fernandes,
  • Monali Manohar,
  • Evan Do,
  • Iris Chang,
  • Alexandra S. Lee,
  • Catherine Blish,
  • Henna Naz Din,
  • Jonasel Roque,
  • Linda N. Geng,
  • Maja Artandi,
  • Mark M. Davis,
  • Neera Ahuja,
  • Samuel S. Yang,
  • Sharon Chinthrajah,
  • Thomas Hagan,
  • Elaine F. Reed,
  • Joanna Schaenman,
  • Ramin Salehi-Rad,
  • Adreanne M. Rivera,
  • Harry C. Pickering,
  • Subha Sen,
  • David Elashoff,
  • Dawn C. Ward,
  • Jenny Brook,
  • Estefania Ramires-Sanchez,
  • Megan Llamas,
  • Claudia Perdomo,
  • Clara E. Magyar,
  • Jennifer Fulcher,
  • David J. Erle,
  • Carolyn S. Calfee,
  • Carolyn M. Hendrickson,
  • Kirsten N. Kangelaris,
  • Viet Nguyen,
  • Deanna Lee,
  • Suzanna Chak,
  • Rajani Ghale,
  • Ana Gonzalez,
  • Alejandra Jauregui,
  • Carolyn Leroux,
  • Luz Torres Altamirano,
  • Ahmad Sadeed Rashid,
  • Andrew Willmore,
  • Prescott G. Woodruff,
  • Matthew F. Krummel,
  • Sidney Carrillo,
  • Alyssa Ward,
  • Charles R. Langelier,
  • Ravi Patel,
  • Michael Wilson,
  • Ravi Dandekar,
  • Bonny Alvarenga,
  • Jayant Rajan,
  • Walter Eckalbar,
  • Andrew W. Schroeder,
  • Gabriela K. Fragiadakis,
  • Alexandra Tsitsiklis,
  • Eran Mick,
  • Yanedth Sanchez Guerrero,
  • Christina Love,
  • Lenka Maliskova,
  • Michael Adkisson,
  • Aleksandra Leligdowicz,
  • Alexander Beagle,
  • Arjun Rao,
  • Austin Sigman,
  • Bushra Samad,
  • Cindy Curiel,
  • Cole Shaw,
  • Gayelan Tietje-Ulrich,
  • Jeff Milush,
  • Jonathan Singer,
  • Joshua J. Vasquez,
  • Kevin Tang,
  • Legna Betancourt,
  • Lekshmi Santhosh,
  • Logan Pierce,
  • Maria Tecero Paz,
  • Michael Matthay,
  • Neeta Thakur,
  • Nicklaus Rodriguez,
  • Nicole Sutter,
  • Norman Jones,
  • Pratik Sinha,
  • Priya Prasad,
  • Raphael Lota,
  • Sadeed Rashid,
  • Saurabh Asthana,
  • Sharvari Bhide,
  • Tasha Lea,
  • Yumiko Abe-Jones,
  • David A. Hafler,
  • Ruth R. Montgomery,
  • Albert C. Shaw,
  • Steven H. Kleinstein,
  • Jeremy P. Gygi,
  • Shrikant Pawar,
  • Anna Konstorum,
  • Ernie Chen,
  • Chris Cotsapas,
  • Xiaomei Wang,
  • Leqi Xu,
  • Charles Dela Cruz,
  • Akiko Iwasaki,
  • Subhasis Mohanty,
  • Allison Nelson,
  • Yujiao Zhao,
  • Shelli Farhadian,
  • Hiromitsu Asashima,
  • Omkar Chaudhary,
  • Andreas Coppi,
  • John Fournier,
  • M. Catherine Muenker,
  • Allison Nelson,
  • Khadir Raddassi,
  • Michael Rainone,
  • William Ruff,
  • Syim Salahuddin,
  • Wade L. Shulz,
  • Pavithra Vijayakumar,
  • Haowei Wang,
  • Esio Wunder Jr.,
  • H. Patrick Young,
  • Albert I. Ko,
  • Xiomei Wang,
  • Denise Esserman,
  • Leying Guan,
  • Anderson Brito,
  • Jessica Rothman,
  • Nathan D. Grubaugh,
  • David B. Corry,
  • Farrah Kheradmand,
  • Li-Zhen Song,
  • Ebony Nelson,
  • Jordan P. Metcalf,
  • Nelson I. Agudelo Higuita,
  • Lauren A. Sinko,
  • J. Leland Booth,
  • Douglas A. Drevets,
  • Brent R. Brown,
  • Monica Kraft,
  • Chris Bime,
  • Jarrod Mosier,
  • Heidi Erickson,
  • Ron Schunk,
  • Hiroki Kimura,
  • Michelle Conway,
  • Dave Francisco,
  • Allyson Molzahn,
  • Connie Cathleen Wilson,
  • Ron Schunk,
  • Trina Hughes,
  • Bianca Sierra,
  • Mark A. Atkinson,
  • Scott C. Brakenridge,
  • Ricardo F. Ungaro,
  • Brittany Roth Manning,
  • Lyle Moldawer,
  • Jordan Oberhaus,
  • Faheem W. Guirgis,
  • Brittney Borresen,
  • Matthew L. Anderson,
  • Lauren I. R. Ehrlich,
  • Esther Melamed,
  • Cole Maguire,
  • Dennis Wylie,
  • Justin F. Rousseau,
  • Kerin C. Hurley,
  • Janelle N. Geltman,
  • Nadia Siles,
  • Jacob E. Rogers,
  • Pablo Guaman Tipan,
  • Michael Agus,
  • Vijay Srinivasan,
  • Ranjit S. Chima,
  • Neal J. Thomas,
  • Simon Li,
  • Alan Pinto,
  • Christopher Newth,
  • Amanda B. Hassinger,
  • Kris Bysani,
  • Edward Vincent Faustino,
  • Eliotte Hirshberg,
  • Kupper Wintergerst,
  • Janice E. Sullivan,
  • Adam Schwarz,
  • Lauren Sorce,
  • Lauren Marsillio,
  • Natalie Cvijanovich,
  • Heidi Flori,
  • Nga Pham,
  • Mary Dahmer,
  • Myke Federman,
  • Kayley Wong,
  • Sitaram S. Vangala,
  • Matteo Pellegrini,
  • Brunilda Balliu,
  • Kinisha P. Gala,
  • Sholeen Nett,
  • Marcy Singleton,
  • Neethi Pinto,
  • Grace Chong,
  • Shirley Viteri,
  • Anil Sapru,
  • Patrick McQuillen,
  • Matt Zinter,
  • Michael Agus,
  • Hrishikesh Kulkarni,
  • Joanna M. Schaenmann,
  • Ramin Salehi-Rad,
  • Michael A. Matthay,
  • Elaine F. Reed,
  • Anil Sapru

摘要

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.