Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity

Pavan K. Bhatraju, MD, MSc; Eric D. Morrell, MD; Ian B. Stanaway, PhD; Neha A. Sathe, MD, MSc; Avantika Srivastava, MS; Radu Postelnicu, MD; Richard Green, BS; Adair Andrews, BSN; Martin Gonzalez, BS; Christopher J. Kratochvil, MD; Vishakha K. Kumar, BS; Tien-Ying Hsiang, PhD; Michael Gale, Jr, PhD; George L. Anesi, MD; David Wyles, MD; M. Jana Broadhurst, MD, PhD; David Brett-Major, MD, MPH; Vikramjit Mukherjee, MD; Jonathan E. Sevransky, MD; Douglas Landsittel, PhD; Chi Hung, MD; William A. Altemeier, MD; Sina A. Gharib, MD; Timothy M. Uyeki, MD, MPH; J. Perren Cobb, MD; Janice M. Liebler, MD; David R. Crosslin, PhD; Gail P. Jarvik, MD; Leopoldo N. Segal, MD; Laura Evans, MD; Carmen Mikacenic, MD; Mark M. Wurfel, MD, PhD

doi:10.1097/CCE.0000000000000827

Critical Care Explorations (Jan 2023)

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity

Pavan K. Bhatraju, MD, MSc,
Eric D. Morrell, MD,
Ian B. Stanaway, PhD,
Neha A. Sathe, MD, MSc,
Avantika Srivastava, MS,
Radu Postelnicu, MD,
Richard Green, BS,
Adair Andrews, BSN,
Martin Gonzalez, BS,
Christopher J. Kratochvil, MD,
Vishakha K. Kumar, BS,
Tien-Ying Hsiang, PhD,
Michael Gale, Jr, PhD,
George L. Anesi, MD,
David Wyles, MD,
M. Jana Broadhurst, MD, PhD,
David Brett-Major, MD, MPH,
Vikramjit Mukherjee, MD,
Jonathan E. Sevransky, MD,
Douglas Landsittel, PhD,
Chi Hung, MD,
William A. Altemeier, MD,
Sina A. Gharib, MD,
Timothy M. Uyeki, MD, MPH,
J. Perren Cobb, MD,
Janice M. Liebler, MD,
David R. Crosslin, PhD,
Gail P. Jarvik, MD,
Leopoldo N. Segal, MD,
Laura Evans, MD,
Carmen Mikacenic, MD,
Mark M. Wurfel, MD, PhD

Affiliations

Pavan K. Bhatraju, MD, MSc: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Eric D. Morrell, MD: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Ian B. Stanaway, PhD: 3 Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Neha A. Sathe, MD, MSc: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Avantika Srivastava, MS: 4 Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
Radu Postelnicu, MD: 5 Division of Pulmonary, Critical Care, and Sleep Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY.
Richard Green, BS: 6 Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA.
Adair Andrews, BSN: 7 Society of Critical Care Medicine, Mount Prospect, IL.
Martin Gonzalez, BS: 7 Society of Critical Care Medicine, Mount Prospect, IL.
Christopher J. Kratochvil, MD: 8 Global Center for Health Security, University of Nebraska Medical Center, Omaha, NE.
Vishakha K. Kumar, BS: 7 Society of Critical Care Medicine, Mount Prospect, IL.
Tien-Ying Hsiang, PhD: 9 Department of Immunology, University of Washington, Seattle, WA.
Michael Gale, Jr, PhD: 9 Department of Immunology, University of Washington, Seattle, WA.
George L. Anesi, MD: 10 Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
David Wyles, MD: 11 Division of Infectious Diseases, Denver Health Medical Center, Denver, CO.
M. Jana Broadhurst, MD, PhD: 8 Global Center for Health Security, University of Nebraska Medical Center, Omaha, NE.
David Brett-Major, MD, MPH: 8 Global Center for Health Security, University of Nebraska Medical Center, Omaha, NE.
Vikramjit Mukherjee, MD: 5 Division of Pulmonary, Critical Care, and Sleep Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY.
Jonathan E. Sevransky, MD: 12 Division of Pulmonary, Allergy, Critical Care and Sleep, School of Medicine, Emory University, Atlanta, GA.
Douglas Landsittel, PhD: 14 Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN.
Chi Hung, MD: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
William A. Altemeier, MD: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Sina A. Gharib, MD: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Timothy M. Uyeki, MD, MPH: 15 Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA.
J. Perren Cobb, MD: 16 Departments of Surgery and Anesthesiology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Janice M. Liebler, MD: 17 Division of Pulmonary, Critical Care and Sleep Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
David R. Crosslin, PhD: 18 Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University, School of Medicine, New Orleans, LA.
Gail P. Jarvik, MD: 6 Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA.
Leopoldo N. Segal, MD: 5 Division of Pulmonary, Critical Care, and Sleep Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY.
Laura Evans, MD: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.
Carmen Mikacenic, MD: 19 Translational Research, Benaroya Research Institute, Seattle, WA.
Mark M. Wurfel, MD, PhD: 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington Medical Center, Seattle, WA.

DOI: https://doi.org/10.1097/CCE.0000000000000827
Journal volume & issue: Vol. 5, no. 1
p. e0827

Abstract

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IMPORTANCE:. Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES:. To assess the role of ANGPTL4 in COVID-19–related outcomes. DESIGN, SETTING, AND PARTICIPANTS:. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES:. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS:. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17–2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10–5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE:. ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

Published in Critical Care Explorations

ISSN: 2639-8028 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Medical emergencies. Critical care. Intensive care. First aid
Website: https://journals.lww.com/ccejournal/pages/default.aspx

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