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

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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 log2increase, 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.

Original languageEnglish (US)
Pages (from-to)E0827
JournalCritical Care Explorations
Issue number1
StatePublished - Dec 30 2022


  • COVID-19
  • angiopoietin-like 4
  • endothelial dysfunction
  • intensive care unit
  • sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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