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Predictive Performance and Clinical Application of COV50, A Urinary Proteomic Biomarker in Early COVID-19 Infection: A Cohort Study

30 Pages Posted: 25 Jan 2022

See all articles by Jan Staessen

Jan Staessen

University of Leuven - Biomedical Sciences Group

Ralph Wendt

St. George Hospital - Department of Infectious Diseases/Tropical Medicine

Yu-Ling Yu

KU Leuven - Research Unit Environment and Health

Sven Kalbitz

St. George Hospital - Department of Infectious Diseases/Tropical Medicine

Lutgarde Thijs

University of Leuven - Research Unit Hypertension and Cardiovascular Epidemiology

Justyna Siwy

Mosaiques-Diagnostics GmbH

Julia Raad

Mosaiques-Diagnostics GmbH

Jochen Metzger

Mosaiques-Diagnostics GmbH

Barbara Neuhaus

Hannover Medical School - Center for Clinical Trials - CTS

Armin Papkalla

Hannover Medical School - Center for Clinical Trials - CTS

Heiko von der Leyen

Hannover Medical School - Center for Clinical Trials - CTS

Alexandre Mebazaa

Hospital Saint Louis-Lariboisière - Department of Anaesthesiology and Intensive Care

Emmanuel Dudoignon

Hospital Saint Louis-Lariboisière - Department of Anaesthesiology and Intensive Care

Goce Spasovski

Ss. Cyril and Methodius University

Mimoza Milenkova

Ss. Cyril and Methodius University

Aleksandra Canevska-Tanevska

Ss. Cyril and Methodius University

Mina Psichogiou

National and Kapodistrian University of Athens - First Department of Internal Medicine

Marek W. Rajzer

Jagiellonian University in Krakow - First Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension

Lukasz Fulawka

Molecular Pathology Centre Cellgen

Magdalena Dzitkowska-Zabielska

Gdansk University of Physical Education and Sport - Faculty of Physical Education

Günter Weiss

Department of Internal Medicine II, Medical University of Innsbruck

Torsten Feldt

Heinrich Heine University Dusseldorf - Clinic of Gastroenterology, Hepatology and Infectious Diseases

Miriam Songa Stegemann

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Johan Normark

University of Umea - Wallenberg Centre for Molecular Medicine

Alexander Zoufaly

Sigmund Freud University Vienna - Department of Medicine IV

Stefan Schmiedel

University Medical Center Hamburg- Eppendorf - Medical Department I and Bernhard-Nocht-Clinic for Tropical Medicine

Michael Seilmaier

München Klinik Schwabing - Department of Haematology, Oncology, Immunology, Palliative Care, Infectious Disease and Tropical Medicine

Benedikt Rumpf

Medical University of Vienna - Nephrology and Dialysis

Miroslaw Banasik

Wroclaw Medical University - Department of Nephrology and Transplantation Medicine

Magdalena Krajewska

Wroclaw Medical University - Department of Nephrology and Transplantation Medicine

Lorenzo Catanese

University of Bayreuth - Department of Nephrology, Angiology and Rheumatology

Harald Rupprecht

Independent

Beata Czerwienska

University of Silesia in Katowice

Björn Peters

Skaraborg Hospital - Department of Nephrology

Asa Nilsson

Skaraborg Hospital - Research and Development Centre

Katja Rothfuss

Robert Bosch Hospital - Margarete-Fischer-Bosch Institute for Clinical Pharmacology and Division of Infectious Diseases,

Christoph Lübbert

Leipzig University Medical Center - Division of Infectious Diseases and Tropical Medicine

Harald Mischak

University of Glasgow - Institute of Cardiovascular and Medical Sciences

Joachim Beige

Martin-Luther-University Halle-Wittenberg

CRIT-Cov-U Investigators

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Abstract

Background: The SARS‑CoV‑2 pandemic remains a worldwide challenge.  The CRIT‑Cov‑U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression.  Following the interim analysis demanded by the German government, the full dataset was analysed to consolidate findings and propose clinical applications. 

Methods: In eight European countries, 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8‑point WHO scale.  Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling.  Statistical methods included logistic regression, receiver operating curve analysis with comparison of the area under curve (AUC) between nested models.  Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalistion costs standardised across countries.  

Findings: The entry WHO scores were 1-3, 4-5 and 6 in 445 (44·0%), 529 (52·3%), and 38 (3·8%) patients, of whom 119 died and 271 progressed.  The standardised odds ratios associated with COV50 for death were 2·44 (95% CI, 2·05-2·92) unadjusted and 1·67 (1·34-2·07) if adjusted for sex, age, body mass index, comorbidities and baseline WHO score, and 1·79 (1·60-2·01) and 1·63 (1·40-1·90), respectively, for disease progression (p<0·0001 for all).  The predictive accuracy of optimised COV50 thresholds were 74·4% (95% CI, 71·6-77·1) for mortality (threshold 0·47) and 67·4% (64·1-70·3) for disease progression (threshold 0·04).  On top of covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·0331) and from 0·697 to 0·730 (p=0·0008) for death and progression, respectively.  Of 196 ambulatory patients, 194 (99·0%) did not reach the 0·04 threshold.  Earlier intervention guided by high-risk COV50 levels should reduce hospital days with cost reductions expressed per 1000 patient-days ranging from M€ 1·208 (95% percentile interval, 1·035-1·406) at low risk (COV50 <0·04) to M€ 4·503 (4·107-4·864) at high risk (COV50 ≥0·04 and age ≥65 years). 

Interpretation: The urinary proteomic COV50 marker is accurate in predicting adverse COVID-19 outcomes.  Even in mild-to-moderate PCR-confirmed infections (WHO scores 1-5), the 0·04 threshold justifies earlier drug treatment, thereby reducing hospitalisation days and costs.

Trial Registration Details: The protocol is deposited at the German Register for Clinical Studies (www.drks.de; number DRKS00022495).

Funding Information: German Federal Ministry of Health acting upon a decree from the German Federal Parliament.

Declaration of Interests: HM, JS and JR are employees of Mosaiques-Diagnostics GmbH, Hannover, Germany. All other authors have nothing to declare.

Ethics Approval Statement: CRIT-Cov-U project complies with the Helsinki declaration. The Ethics Committee of the German-Saxonian Board of Physicians, Dresden, Germany (number, EK-BR-88/20.1) and the Institutional Review Boards of the recruiting sites provided ethical clearance.

Keywords: COVID-19, disease severity, risk score, SARS-CoV-2, urinary proteomics, World Health Organization ordinal scale

Suggested Citation

Staessen, Jan and Wendt, Ralph and Yu, Yu-Ling and Kalbitz, Sven and Thijs, Lutgarde and Siwy, Justyna and Raad, Julia and Metzger, Jochen and Neuhaus, Barbara and Papkalla, Armin and von der Leyen, Heiko and Mebazaa, Alexandre and Dudoignon, Emmanuel and Spasovski, Goce and Milenkova, Mimoza and Canevska-Tanevska, Aleksandra and Psichogiou, Mina and Rajzer, Marek W. and Fulawka, Lukasz and Dzitkowska-Zabielska, Magdalena and Weiss, Günter and Feldt, Torsten and Stegemann, Miriam Songa and Normark, Johan and Zoufaly, Alexander and Schmiedel, Stefan and Seilmaier, Michael and Rumpf, Benedikt and Banasik, Miroslaw and Krajewska, Magdalena and Catanese, Lorenzo and Rupprecht, Harald and Czerwienska, Beata and Peters, Björn and Nilsson, Asa and Rothfuss, Katja and Lübbert, Christoph and Mischak, Harald and Beige, Joachim and Investigators, CRIT-Cov-U, Predictive Performance and Clinical Application of COV50, A Urinary Proteomic Biomarker in Early COVID-19 Infection: A Cohort Study. Available at SSRN: https://ssrn.com/abstract=4006139 or http://dx.doi.org/10.2139/ssrn.4006139

Jan Staessen (Contact Author)

University of Leuven - Biomedical Sciences Group ( email )

Celestijnenlaan 200F
B-3001
Leuven
Belgium

Ralph Wendt

St. George Hospital - Department of Infectious Diseases/Tropical Medicine ( email )

Leipzig
Germany

Yu-Ling Yu

KU Leuven - Research Unit Environment and Health ( email )

Belgium

Sven Kalbitz

St. George Hospital - Department of Infectious Diseases/Tropical Medicine ( email )

Leipzig
Germany

Lutgarde Thijs

University of Leuven - Research Unit Hypertension and Cardiovascular Epidemiology ( email )

Leuven
Belgium

Justyna Siwy

Mosaiques-Diagnostics GmbH ( email )

Hannover
Germany

Julia Raad

Mosaiques-Diagnostics GmbH ( email )

Hannover
Germany

Jochen Metzger

Mosaiques-Diagnostics GmbH ( email )

Barbara Neuhaus

Hannover Medical School - Center for Clinical Trials - CTS ( email )

Hannover
Germany

Armin Papkalla

Hannover Medical School - Center for Clinical Trials - CTS ( email )

Hannover
Germany

Heiko Von der Leyen

Hannover Medical School - Center for Clinical Trials - CTS ( email )

Hannover
Germany

Alexandre Mebazaa

Hospital Saint Louis-Lariboisière - Department of Anaesthesiology and Intensive Care ( email )

Paris
France

Emmanuel Dudoignon

Hospital Saint Louis-Lariboisière - Department of Anaesthesiology and Intensive Care ( email )

Paris
France

Goce Spasovski

Ss. Cyril and Methodius University ( email )

blvd. Goce Delcev 9
Skopje, 1000
Macedonia

Mimoza Milenkova

Ss. Cyril and Methodius University ( email )

blvd. Goce Delcev 9
Skopje, 1000
Macedonia

Aleksandra Canevska-Tanevska

Ss. Cyril and Methodius University ( email )

blvd. Goce Delcev 9
Skopje, 1000
Macedonia

Mina Psichogiou

National and Kapodistrian University of Athens - First Department of Internal Medicine

Athens
Greece

Marek W. Rajzer

Jagiellonian University in Krakow - First Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension ( email )

Kraków
Poland

Lukasz Fulawka

Molecular Pathology Centre Cellgen ( email )

Wroclaw
Poland

Magdalena Dzitkowska-Zabielska

Gdansk University of Physical Education and Sport - Faculty of Physical Education ( email )

Gdańsk
Poland

Günter Weiss

Department of Internal Medicine II, Medical University of Innsbruck ( email )

Torsten Feldt

Heinrich Heine University Dusseldorf - Clinic of Gastroenterology, Hepatology and Infectious Diseases ( email )

Düsseldorf
Germany

Miriam Songa Stegemann

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine ( email )

Berlin
Germany

Johan Normark

University of Umea - Wallenberg Centre for Molecular Medicine ( email )

Umeå
Sweden

Alexander Zoufaly

Sigmund Freud University Vienna - Department of Medicine IV ( email )

Vienna
Austria

Stefan Schmiedel

University Medical Center Hamburg- Eppendorf - Medical Department I and Bernhard-Nocht-Clinic for Tropical Medicine ( email )

Hamburg
Germany

Michael Seilmaier

München Klinik Schwabing - Department of Haematology, Oncology, Immunology, Palliative Care, Infectious Disease and Tropical Medicine ( email )

München
Germany

Benedikt Rumpf

Medical University of Vienna - Nephrology and Dialysis ( email )

Vienna
Austria

Miroslaw Banasik

Wroclaw Medical University - Department of Nephrology and Transplantation Medicine ( email )

Wroclaw
Poland

Magdalena Krajewska

Wroclaw Medical University - Department of Nephrology and Transplantation Medicine ( email )

Wroclaw
Poland

Lorenzo Catanese

University of Bayreuth - Department of Nephrology, Angiology and Rheumatology ( email )

Bayreuth
Germany

Harald Rupprecht

Independent ( email )

Beata Czerwienska

University of Silesia in Katowice ( email )

ul. Okólna 89F
Częstochowa, 42-200
Poland

Björn Peters

Skaraborg Hospital - Department of Nephrology

Sweden

Asa Nilsson

Skaraborg Hospital - Research and Development Centre ( email )

Skövde
Sweden

Katja Rothfuss

Robert Bosch Hospital - Margarete-Fischer-Bosch Institute for Clinical Pharmacology and Division of Infectious Diseases, ( email )

Stuttgart
Germany

Christoph Lübbert

Leipzig University Medical Center - Division of Infectious Diseases and Tropical Medicine ( email )

Leipzig
Germany

Harald Mischak

University of Glasgow - Institute of Cardiovascular and Medical Sciences ( email )

Glasgow, Scotland
United Kingdom

Joachim Beige

Martin-Luther-University Halle-Wittenberg ( email )

Germany

No contact information is available for CRIT-Cov-U Investigators

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