Evidence from fatal COVID-19 for targeting the bradykinin metabolism - a single-center cohort study

Abstract

Background Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called “bradykinin-storm”. However, clinical investigations of bradykinin, its metabolite des-Arg9-bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients. A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020 – 02/2021; prevalent wildtype SARS CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg9-bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and non-survivors (n = 23) of COVID-19 from admission until discharge or death. Results We found significantly higher plasma levels of des-Arg9-bradykinin in survivors and non-survivors of COVID-19 compared to healthy controls. In addition, plasma des-Arg9-bradykinin levels were higher (p < 0.001; effect size = 0.79) in non-survivors compared to survivors of COVID-19, and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or LDH, and outcome. Consequently, compared to healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and non-survivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced (p < 0.001; effect size = 0.7) in non-survivors compared to survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and non-survivors of COVID-19. Conclusions In conclusion, our data demonstrates that des-Arg9-bradykinin is significantly elevated in COVID-19 ICU patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg9-bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg9-bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.