Biomarkers of Cardiac Injury, Renal Injury, and Inflammation Are Strong Mediators of Sex-Associated Death in COVID-19

BACKGROUND: Studies examining outcomes among individuals with COronaVIrus Disease 2019 (COVID-19) have consistently demonstrated that men have worse outcomes than women, with a higher incidence of myocardial injury, respiratory failure, and death. However, mechanisms of higher morbidity and mortality among men remain poorly understood. We aimed to identify mediators of the relationship between sex and COVID-19-associated mortality. METHODS: Patients hospitalized at two quaternary care facilities, New York Presbyterian Hospital (CUIMC/NYPH) and Massachusetts General Hospital (MGH), for SARS-CoV-2 infection between February and May 2020 were included. Five independent biomarkers were identified as mediators of sex effects, including high-sensitivity cardiac troponin T (hs-cTNT), high sensitivity C-reactive protein (hs-CRP), ferritin, D-dimer, and creatinine. RESULTS: In the CUIMC/NYPH cohort (n = 2,626, 43% female), male sex was associated with significantly greater mortality (26 vs. 21%, p = 0.0146) and higher peak hs-cTNT, hs-CRP, ferritin, D-dimer, and creatinine (p < 0.001). The effect of male sex on the primary outcome of death was partially mediated by peak values of all five biomarkers, suggesting that each pathophysiological pathway may contribute to increased risk of death in men. Hs-cTnT, creatinine, and hs-CRP were the strongest mediators. Findings were highly consistent in the MGH cohort with the exception of D-dimer. CONCLUSIONS: This study suggests that the effect of sex on COVID-19 outcomes is mediated by cardiac and kidney injury, as well as underlying differences in inflammation and iron metabolism. Exploration of these specific pathways may facilitate sex-directed diagnostic and therapeutic strategies for patients with COVID-19 and provides a framework for the study of sex differences in other complex diseases.