. 2025 Feb:85:154950.

doi: 10.1016/j.jcrc.2024.154950. Epub 2024 Nov 14.

Shock prediction with dipeptidyl peptidase-3 and renin (SPiDeR) in hypoxemic patients with COVID-19

Laurence W Busse¹, J Pedro Teixeira², Christopher L Schaich³, Caitlin C Ten Lohuis⁴, Nathan D Nielsen⁵, Jeffrey M Sturek⁶, Lisa H Merck⁷, Wesley H Self⁸, Michael A Puskarich⁹, Akram Khan¹⁰, Matthew W Semler¹¹, Ari Moskowitz¹², David N Hager¹³, Abhijit Duggal¹⁴, Todd W Rice¹¹, Adit A Ginde¹⁵, Brian R Tiffany¹⁶, Nicole M Iovine¹⁷, Peter Chen¹⁸, Basmah Safdar¹⁹, Kevin W Gibbs²⁰, Ali Javaheri²¹, Marjolein de Wit²², Michelle S Harkins²³, Meghan M Joly²⁴, Sean P Collins⁸; ACTIV-4 Host Tissue Investigators

Affiliations

¹ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA; Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
² Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA. Electronic address: jteixeira@salud.unm.edu.
³ Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁴ Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
⁵ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA; Section of Transfusion Medicine and Therapeutic Pathology, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁶ Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
⁷ Department of Emergency Medicine, Virginia Commonwealth University, Richmond, VA, USA.
⁸ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Emergency Medicine, Hennepin Healthcare, Minneapolis, MN, USA.
¹⁰ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
¹¹ Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Division of Critical Care, Montefiore Medical Center, The Bronx, NY, USA.
¹³ Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Department of Critical Care Medicine, Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁵ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁶ Chandler Regional Medical Center, Chandler, AZ, USA.
¹⁷ University of Florida Health, Gainesville, FL, USA.
¹⁸ Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁹ Department of Emergency Medicine, Yale School of Medicine, New Haven, CT, USA.
²⁰ Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²¹ Department of Medicine, Washington University, Saint Louis, MO, USA.
²² Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
²³ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
²⁴ Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.

PMID: 39546997
PMCID: PMC11697573 (available on 2026-02-01)
DOI: 10.1016/j.jcrc.2024.154950

Shock prediction with dipeptidyl peptidase-3 and renin (SPiDeR) in hypoxemic patients with COVID-19

Laurence W Busse et al. J Crit Care. 2025 Feb.

. 2025 Feb:85:154950.

doi: 10.1016/j.jcrc.2024.154950. Epub 2024 Nov 14.

Authors

Affiliations

¹ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA; Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
² Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA. Electronic address: jteixeira@salud.unm.edu.
³ Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁴ Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
⁵ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA; Section of Transfusion Medicine and Therapeutic Pathology, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁶ Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
⁷ Department of Emergency Medicine, Virginia Commonwealth University, Richmond, VA, USA.
⁸ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Emergency Medicine, Hennepin Healthcare, Minneapolis, MN, USA.
¹⁰ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
¹¹ Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Division of Critical Care, Montefiore Medical Center, The Bronx, NY, USA.
¹³ Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Department of Critical Care Medicine, Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁵ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁶ Chandler Regional Medical Center, Chandler, AZ, USA.
¹⁷ University of Florida Health, Gainesville, FL, USA.
¹⁸ Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁹ Department of Emergency Medicine, Yale School of Medicine, New Haven, CT, USA.
²⁰ Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²¹ Department of Medicine, Washington University, Saint Louis, MO, USA.
²² Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
²³ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
²⁴ Vanderbilt Institute of Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.

PMID: 39546997
PMCID: PMC11697573 (available on 2026-02-01)
DOI: 10.1016/j.jcrc.2024.154950

Abstract

Background: Plasma dipeptidyl peptidase-3 (DPP3) and renin levels are associated with organ dysfunction and mortality. However, whether these biomarkers are associated with the subsequent onset of shock in at-risk patients is unknown.

Methods: Using plasma samples collected from participants enrolled in the fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines Host Tissue platform trial, we measured DPP3 and renin in 184 subjects hospitalized with acute hypoxemia from COVID-19 without baseline vasopressor requirement. We calculated the odds ratio of development of shock (defined as the initiation of vasopressor therapy) by Day 28 based on Day 0 DPP3 and renin levels.

Results: Subjects with DPP3 above the median had a significantly higher incidence of vasopressor initiation within 28 days (28.4 % vs. 16.7 %, p = 0.031) and higher 28-day mortality (25.0 % vs. 6.7 %, p < 0.001). After adjusting for covariables, DPP3 above the median was associated with shorter time to vasopressor initiation, greater 28-day mortality, fewer vasopressor-free days, and greater odds of a hypotensive event over 7 days. Significant associations were not observed for renin.

Conclusions: In patients hospitalized with COVID-19 and hypoxemia without baseline hypotension, higher baseline plasma levels of DPP3 but not renin were associated with increased risk of subsequent shock and death.

Keywords: Biomarker; COVID-19; Clinical trial registered on June 10, 2021, on www.clinicaltrials.gov (NCT04924660).; Dipeptidyl peptidase-3; Renin; Septic shock.

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Conflict of interest statement

Declaration of competing interest All authors completed and submitted the ICMJE form for disclosure of potential conflicts of interest.

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The circulating renin-angiotensin system and mortality among patients hospitalized for COVID-19: a mechanistic substudy of the ACTIV-4 Host Tissue trials.
Schaich CL, Chappell MC, Shotwell MS, Joly MM, Gibbs KW, Barksdale A, Douglas IS, Chen P, Levitt JE, Puskarich MA, Rice TW, Harkins MS, Hudock KM, Lanspa MJ, Ginde AA, Self WH, Collins SP, Files DC; ACTIV-4 Host Tissue Investigators. Schaich CL, et al. Am J Physiol Lung Cell Mol Physiol. 2025 Mar 1;328(3):L405-L412. doi: 10.1152/ajplung.00372.2024. Epub 2025 Jan 30. Am J Physiol Lung Cell Mol Physiol. 2025. PMID: 39884670 Free PMC article.

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Shock prediction with dipeptidyl peptidase-3 and renin (SPiDeR) in hypoxemic patients with COVID-19

Affiliations

Shock prediction with dipeptidyl peptidase-3 and renin (SPiDeR) in hypoxemic patients with COVID-19

Authors

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Abstract

Conflict of interest statement

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