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The Lancet. Digital health
10, 2022;4 (10): e727-e737.

Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study.

Jan A Staessen, Ralph Wendt, Yu-Ling Yu, Sven Kalbitz, Lutgarde Thijs, Justyna Siwy, Julia Raad, Jochen Metzger, Barbara Neuhaus, Armin Papkalla, Heiko von der Leyen, Alexandre Mebazaa, Emmanuel Dudoignon, Goce Spasovski, Mimoza Milenkova, Aleksandra Canevska-Taneska, Mercedes Salgueira Lazo, Mina Psichogiou, Marek W Rajzer, Łukasz Fuławka, Magdalena Dzitkowska-Zabielska, Guenter Weiss, Torsten Feldt, Miriam Stegemann, Johan Normark, Alexander Zoufaly, Stefan Schmiedel, Michael Seilmaier, Benedikt Rumpf, Mirosław Banasik, Magdalena Krajewska, Lorenzo Catanese, Harald D Rupprecht, Beata Czerwieńska, Björn Peters, Åsa Nilsson, Katja Rothfuss, Christoph Lübbert, Harald Mischak, Joachim Beige, CRIT-CoV-U investigators
Author Information
  1. Jan A Staessen: Non-Profit Research Institute Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium; Biomedical Sciences Group, Faculty of Medicine, University of Leuven, Leuven, Belgium.
  2. Ralph Wendt: Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany.
  3. Yu-Ling Yu: Research Unit Environment and Health, Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium.
  4. Sven Kalbitz: Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany.
  5. Lutgarde Thijs: Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
  6. Justyna Siwy: Mosaiques-Diagnostics, Hannover, Germany.
  7. Julia Raad: Mosaiques-Diagnostics, Hannover, Germany.
  8. Jochen Metzger: Mosaiques-Diagnostics, Hannover, Germany.
  9. Barbara Neuhaus: Centre for Clinical Trials, Medizinische Hochschule, Hannover, Germany.
  10. Armin Papkalla: Centre for Clinical Trials, Medizinische Hochschule, Hannover, Germany.
  11. Heiko von der Leyen: Centre for Clinical Trials, Medizinische Hochschule, Hannover, Germany.
  12. Alexandre Mebazaa: Department of Anaesthesiology and Intensive Care, Hospital Saint Louis-Lariboisière, Paris, France.
  13. Emmanuel Dudoignon: Department of Anaesthesiology and Intensive Care, Hospital Saint Louis-Lariboisière, Paris, France.
  14. Goce Spasovski: Cyril and Methodius University, Skopje, North Macedonia.
  15. Mimoza Milenkova: Cyril and Methodius University, Skopje, North Macedonia.
  16. Aleksandra Canevska-Taneska: Cyril and Methodius University, Skopje, North Macedonia.
  17. Mercedes Salgueira Lazo: Hospital Virgen Macarena, Sevilla, Spain.
  18. Mina Psichogiou: First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
  19. Marek W Rajzer: First Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jagiellonian University Medical College, Kraków, Poland.
  20. Łukasz Fuławka: Molecular Pathology Centre Cellgen, Wrocław, Poland.
  21. Magdalena Dzitkowska-Zabielska: Faculty of Physical Education, Gdańsk University of Physical Education and Sport and Centre of Translational Medicine, Medical University of Gdańsk, Gdańsk, Poland.
  22. Guenter Weiss: Department of Internal Medicine II, Medical University Innsbruck, Innsbruck, Austria.
  23. Torsten Feldt: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany.
  24. Miriam Stegemann: Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  25. Johan Normark: Wallenberg Centre for Molecular Medicine, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
  26. Alexander Zoufaly: Department of Medicine IV, Clinic Favoriten and Faculty of Medicine, Sigmund Freud University, Vienna, Austria.
  27. Stefan Schmiedel: Medical Department I and Bernhard-Nocht-Clinic for Tropical Medicine, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.
  28. Michael Seilmaier: Department of Haematology, Oncology, Immunology, Palliative Care, Infectious Disease and Tropical Medicine, München Klinik Schwabing, München, Germany.
  29. Benedikt Rumpf: Nephrology and Dialysis, Internal Medicine III, Medical University of Vienna, Vienna, Austria.
  30. Mirosław Banasik: Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland.
  31. Magdalena Krajewska: Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland.
  32. Lorenzo Catanese: Department of Nephrology, Angiology and Rheumatology, Hospital Bayreuth, Bayreuth, Germany.
  33. Harald D Rupprecht: Department of Nephrology, Angiology and Rheumatology, Hospital Bayreuth, Bayreuth, Germany.
  34. Beata Czerwieńska: University of Silesia, Katowice, Poland.
  35. Björn Peters: Department of Nephrology, Skaraborg Hospital, Skövde and Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Research and Development Centre, Skaraborg Hospital, Skövde, Sweden.
  36. Åsa Nilsson: Research and Development Centre, Skaraborg Hospital, Skövde, Sweden.
  37. Katja Rothfuss: Department of Gastroenterology, Hepatology and Endocrinology, Robert Bosch Hospital, Stuttgart, Germany.
  38. Christoph Lübbert: Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany; Division of Infectious Diseases and Tropical Medicine, Leipzig University Medical Centre, Leipzig, Germany.
  39. Harald Mischak: Mosaiques-Diagnostics, Hannover, Germany; Institute of Cardiovascular and Medical Sciences, Glasgow, UK.
  40. Joachim Beige: Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany; Martin-Luther-University Halle-Wittenberg, Halle an der Saale, Halle, Germany. Electronic address: joachim.beige@kfh.de.
PMID: 36057526 DOI: 10.1016/S2589-7500(22)00150-9

Abstract

BACKGROUND: The SARS-CoV-2 pandemic is 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 from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker.
METHODS: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 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 and receiver operating characteristic curve analysis with a 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 hospitalisation costs adjusted for the gross per capita domestic product of each country.
FINDINGS: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1-3 in 445 (44%) participants, 4-5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05-2·92) unadjusted and 1·67 (1·34-2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60-2·01) when unadjusted and 1·63 (1·41-1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6-77·1%) for mortality (threshold 0·47) and 67·4% (64·4-70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5-95% percentile interval 0·730-1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04).
INTERPRETATION: The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1-4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs.
FUNDING: German Federal Ministry of Health.

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Grants

  1. KLI 861/Austrian Science Fund FWF

MeSH Term

Adult
Biomarkers
COVID-19
Cohort Studies
Disease Progression
Humans
Pilot Projects
Prospective Studies
Proteomics
SARS-CoV-2

Chemicals

Biomarkers
Journal Article Multicenter Study Research Support, Non-U.S. Gov't
Article has an altmetric score of 78

Word Cloud

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