Circulating dipeptidyl peptidase 3 and bio-adrenomedullin levels are associated with impaired outcomes in critically ill COVID-19 patients: a prospective international multicentre study.

Dipeptidyl peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. The objectives of the present study were to investigate associations of bio-ADM and "circulating DPP3" (cDPP3) with short-term outcome in critically ill COVID-19 patients (n=80). A multicentre prospective cohort study was performed. The primary end-point was 28-day mortality. Secondary end-points included different severities of acute kidney injury (AKI). cDPP3 levels were mainly associated with 28-day mortality; Area under the receiver operating characteristics (AUROCs) of 0.69 (0.56-0.82, p=0.023), 0.77 (0.64-0.90, p<0.001) and 0.81 (0.65-0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI, with AUROCs of 0.64 (0.51-0.77, p=0.048), 0.75 (0.64-0.86, p<0.001) and 0.83 (0.74-0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day mortality (hazard ratio 11.8; 95% CI 2.5-55.3, p<0.001). cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM-related pathways may improve outcome of COVID-19.

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Déclaration de conflit d'intérêts

Conflict of interest: Analyses of samples was performed free of charge by the respective biomarker companies (Sphingotec for bio-ADM and 4TEEN4 for cDPP3). No additional funding was provided for the execution of this study. Both biomarker-companies had no role in the design of the study, its execution or analyses, interpretation of the data, or the decision to submit results. D. van Lier was invited to a meeting in Berlin by 4TEEN4 Pharmaceuticals GmbH. B. Deniau was invited to a meeting in Henningsdorf by 4TEEN4 Pharmaceuticals GmbH. K. Santos is employed by 4TEEN4 Pharmaceuticals, the company holding patent rights for the DPP3 assay. O. Hartmann is employed by Sphingotec GmbH, the company holding patent rights for the bio-ADM assay and a licence to commercialise the cDPP3 assay. E. Dudoignon, F. Depret and B. Plaud have nothing to declare. P-F. Laterre, A. Mebazaa and P. Pickkers received travel and consultancy reimbursements from 4TEEN4 and Sphingotec, the companies holding patent rights for the DPP3 and bio-ADM assays used in the study, respectively.