RAGE has potential pathogenetic and prognostic value in nonintubated hospitalized patients with COVID-19

Katherine D. Wick, Lianne Siegel, James D. Neaton, Cathryn Oldmixon, Jens Lundgren, Robin L. Dewar, H. Clifford Lane, B. Taylor Thompson, Michael A. Matthay

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1 Scopus citations

Abstract

BACKGROUND. The value of the soluble receptor for advanced glycation end-products (sRAGE) as a biomarker in COVID-19 is not well understood. We tested the association between plasma sRAGE and illness severity, viral burden, and clinical outcomes in hospitalized patients with COVID-19 who were not mechanically ventilated. METHODS. Baseline sRAGE was measured among participants enrolled in the ACTIV-3/TICO trial of bamlanivimab for hospitalized patients with COVID-19. Spearman's rank correlation was used to assess the relationship between sRAGE and other plasma biomarkers, including viral nucleocapsid antigen. Fine-Gray models adjusted for baseline supplemental oxygen requirement, antigen level, positive endogenous anti-nucleocapsid antibody response, sex, age, BMI, diabetes mellitus, renal impairment, corticosteroid treatment, and log2-transformed IL-6 level were used to assess the association between baseline sRAGE and time to sustained recovery. Cox regression adjusted for the same factors was used to assess the association between sRAGE and mortality. RESULTS. Among 277 participants, baseline sRAGE was strongly correlated with viral plasma antigen concentration (ρ = 0.57). There was a weaker correlation between sRAGE and biomarkers of systemic inflammation, such as IL-6 (ρ = 0.36) and CRP (ρ = 0.20). Participants with plasma sRAGE in the highest quartile had a significantly lower rate of sustained recovery (adjusted recovery rate ratio, 0.64 [95% CI, 0.43-0.90]) and a higher unadjusted risk of death (HR, 4.70 [95% CI, 2.01- 10.99]) compared with participants in the lower quartiles. CONCLUSION. Elevated plasma sRAGE in hospitalized, nonventilated patients with COVID-19 was an indicator of both clinical illness severity and plasma viral load. Plasma sRAGE in the highest quartile was associated with a lower likelihood of sustained recovery and higher unadjusted risk of death. These findings, which we believe to be novel, indicate that plasma sRAGE may be a promising biomarker for COVID-19 prognostication and clinical trial enrichment.

Original languageEnglish (US)
Article numbere157499
JournalJCI Insight
Volume7
Issue number9
DOIs
StatePublished - May 9 2022

Bibliographical note

Funding Information:
support from NIH grant 18X107CF6 through a contract with Leidos Biomedical. JDN declares research support from the NIH and NIAID through a contract with Leidos Biomedical. RLD declares support from NIH grant HHSN261201500003I through a contract with Leidos Biomedical. BTT declares personal fees from Bayer, Novartis Pharmaceuticals, and Genentech and participation in data safety monitoring for the NIH, Canadian Institutes of Health Research, the Department of Defense, and the University of Toronto. MAM declares research grants from Genentech-Roche and Quantum Leap Healthcare collaborative and personal fees from Citius Pharmaceuticals, Novartis Pharmaceuticals, Johnson & Johnson Pharmaceuticals, and Pliant Therapeutics.

Funding Information:
KDW acknowledges support from NIH grant 5T32GM008440-24. LS acknowledges support from NIH grant 18X107CF6 through a contract with Leidos Biomedical. JDN acknowledges support from the NIH and NIAID through a contract with Leidos Biomedical. RLD acknowledges support from NIH grant HHSN261201500003I through a contract with Leidos Biomedical. BTT acknowledges research support from the NIH/National Heart, Lung, and Blood Institute (NIH/NHLBI). MAM acknowledges support from the NIH/NHLBI (grant R35HL140026) and NIH/NIAID (grant OT2HL156812) as well as from research grants from Genentech-Roche and Quantum Leap Healthcare collaborative. We would like to acknowledge all members of the ACTIV-3/TICO LY-CoV555 study group and the NIH/NIAID for the conduct and support of the original trial. See Supplemental Acknowledgments for details on the TICO study group.

Publisher Copyright:
© 2022, Wick et al.

Keywords

  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Biomarkers
  • COVID-19
  • Humans
  • Interleukin-6
  • Prognosis
  • Receptor for Advanced Glycation End Products

PubMed: MeSH publication types

  • Clinical Trial
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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