Angiogenesis 2022 Jun 20. Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study Alexandros Rovas # 1, Konrad Buscher # 1, Irina Osiaevi 1 2, Carolin Christina Drost 1, Jan Sackarnd 3, Phil-Robin Tepasse 4, Manfred Fobker 5, Joachim Kühn 6, Stephan Braune 7, Ulrich Göbel 8, Gerold Thölking 1 9, Andreas Gröschel 10, Jan Rossaint 11, Hans Vink 12, Alexander Lukasz 1, Hermann Pavenstädt 1, Philipp Kümpers 13 Affiliations 1Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. 2Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. 3Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. 4Department of Medicine B for Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. 5Center for Laboratory Medicine, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. 6Institute of Virology, University Hospital Münster, Von-Stauffenberg-Straße 36, 48151, Münster, Germany. 7Departmenf of Intensive Care and Emergency Medicine, St. Franziskus-Hospital GmbH, Hohenzollernring 70, 48145, Münster, Germany. 8Department of Anaesthesiology and Critical Care, St. Franziskus-Hospital GmbH, Hohenzollernring 70, 48145, Münster, Germany. 9Department of Internal Medicine and Nephrology, University Hospital Münster Marienhospital Steinfurt, Mauritiusstr. 5, 48565, Steinfurt, Germany. 10Department of Pulmonology, Clemens Hospital, Düesbergweg 124, 48153, Münster, Germany. 11Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. 12Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER, Maastricht, the Netherlands. 13Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany. philipp.kuempers@ukmuenster.de.
Contributed equally.
Abstract Aims: Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. Methods and results: This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19. Conclusion: Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes. Keywords: Biomarker; COVID-19; Microcirculation; Microvascular dysfunction; Proteomic signature; Sepsis.
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