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.