Soluble Dipeptidyl-Peptidase 4 (sDPP4) Serum Activity Is Associated With the Severity of COVID-19 Disease and is a Strong Prognostic Biomarker of Mortality

Background: Type 2 diabetes mellitus (T2DM) and obesity are risk factors of COVID-19 disease course. Retrospective observational analyses reported improvement in COVID-19 severe outcomes and mortality in T2DM patients using a DPP4 inhibitor. However, little is known about the prognostic value of circulating soluble DPP4 activity in patients with SARS-CoV-2 infection. Methods: We conducted an observational, retrospective cohort study with 184 Hungarian adults. Hospitalized patients with acute COVID-19 disease (n=102) and plasma donors (n=43) recovered from prior SARS-CoV-2 infection were enrolled from April to July, 2020 at two institutions in Budapest. “Non-COVID-19 controls” (n=39) were employed with serum sDPP4 activity determined from samples taken before September, 2019. Duplicate serum sDPP4 activity determinations by microplate base enzyme kinetic assay were successful in 182 individuals from different COVID-19 disease severity groups (acute COVID-19 patients were classified into 4 and plasma donors into 2 categories based on peak severity). Findings: A significant difference in sDPP4 activity was found among study groups (p<0·0001): acute SARS-CoV-2 infected group (n=100, median=23·24 U/L [IQR 17·8-30·34]) vs all non-acutely ill participants (n=82, median=35·62 U/L [IQR 31·17-42·09], and plasma donors (median=40·16 U/L [IQR 34·28-49·49], both p-values<0·0001). sDPP4 activity was lower in hospitalized patients with acute SARS-CoV-2 who died (n=24, median=17·08 U/L, [IQR 16·47-22·12]) vs survivors (n=76, median=25·08 U/L [IQR 20·21-30·80], p<0·0001). Logistic regression (p=0·0023) indicated that sDPP4 activity is a prognostic biomarker of mortality. ROC AUC of 73·33% (95%CI: 61·98%-84·68%, p[area=0·5]<0·0001), and 83·45% (95%CI: 74·48%-92·51%, p[area=0·5]<0·0001) characterized the sDPP4 activity test (cut-off 22·25 U/L) and in combination with age in predicting death (median 9·5 days prior) among hospitalized patients with acute COVID-19 disease, respectively. Interpretation: We concluded that serum sDPP4 activity is associated with the severity and a strong biomarker of mortality in COVID-19 disease. Funding Information: Ramgen funded the sDPP4 activity measurement and related costs in the study. Declaration of Interests: Semmelweis University and Central Hospital of Southern Pest, National Institute for Infectious Diseases and Haematology has entered into a contractual partnership with Ramgen to conduct this research and they submitted a patent application (HIPO Ref: 311174000-20210226-1522-004576, inventors: GF, ZP, IVN). AN reports a prior fellowship at the Semmelweis University - Racz Karoly Doctoral School which ended prior to the initiation of this project for which he was contracted with Ramgen. IB reports institutional grants or contracts form Envision 2000 and EuroPN (Fresenius Kabi). BL reports payment or honoraria from GlaxoSmithKline, MSD, Fresenius-Kabi, Gilead Sciences, outside of the submitted work. MA reports an associate professor position of Eotvos Lorand University, Faculty of Science, Department of Probability Theory and Statistics, Institute of Mathematics and that he was separately contracted with Ramgen unconnected to his other employments. TM reports on a data safety monitoring board or advisory board participation at AbbVie, BMS, Janssen-Cilag, Novartis, Pfizer, Takeda. CG reports stocks in Ramgen and other interests as co-CEO in Ramgen. BM reports institutional payments from Medtronic, Boston Scientific; personal fees from Biotronik, Abbott, AstraZeneca, Boehringer Ingelheim, and Novartis, outside of the submitted work. PF reports leadership role as President of Hungarian Society for Experimental and Clinical Pharmacology; and other interests as the founder, and CEO of PharmaHungary Group, outside of the submitted work. VNI reports grants or contracts from National Research, Development and Innovation Office, National Research, Development and Innovation Office / Ministry of Innovation and Technology, and Ministry of Human Capacities, outside of the submitted work. GF reports a paid part time employment at the Semmelweis University- Eotvos Lorand Research Network (Molecular Medicine Study group, Hungarian Academy of Sciences, where his employer did not declare employee conflict of interest for this independently conducted project); support for attending meetings and personal fees from 77 Elektronika, and Diabetes and Metabolism Foundation, outside of the submitted work; stocks in Biomerieux and Ramgen and other interests as co-CEO in Ramgen. All the other authors have nothing to declare. Ethics Approval Statement: Study participants signed the informed consent for the whole project and all the sample collections as well as the subsequent study on sDPP4 activity conducted by Ramgen possessed the ethical approval of the national ethical body of Hungary (Medical Research Council Scientific and Research Committee, reference: IV/4403-4/2020/EKU; December 30, 2020). The study was conducted according to the declaration of Helsinki.