The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling
Maximilian Ackermann,
Jan C. Kamp,
Christopher Werlein,
Claire L. Walsh,
Helge Stark,
Verena Prade,
Rambabu Surabattula,
Willi L. Wagner,
Catherine Disney,
Andrew J. Bodey,
Thomas Illig,
Diana J. Leeming,
Morten A. Karsdal,
Alexandar Tzankov,
Peter Boor,
Mark P. Kühnel,
Florian P. Länger,
Stijn E. Verleden,
Hans M. Kvasnicka,
Hans H. Kreipe,
Axel Haverich,
Stephen M. Black,
Axel Walch,
Paul Tafforeau,
Peter D. Lee,
Marius M. Hoeper,
Tobias Welte,
Benjamin Seeliger,
Sascha David,
Detlef Schuppan,
Steven J. Mentzer,
Danny D. Jonigk
Affiliations
Maximilian Ackermann
Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Germany; Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany
Jan C. Kamp
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
Christopher Werlein
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Institute of Pathology, Hannover Medical School, Hannover, Germany
Claire L. Walsh
Centre for Advanced Biomedical Imaging, University College London, UK
Helge Stark
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Institute of Pathology, Hannover Medical School, Hannover, Germany
Verena Prade
Research Unit Analytical Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
Rambabu Surabattula
Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
Willi L. Wagner
Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; Member of the German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TLRC), Heidelberg, Germany
Catherine Disney
Department of Mechanical Engineering, University College London, UK
Andrew J. Bodey
Diamond Light Source, Oxfordshire, Oxford, UK
Thomas Illig
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover Medical School, Germany
Diana J. Leeming
Hannover Unified Biobank, Hannover Medical School, Hannover Medical School, Germany
Morten A. Karsdal
Nordic Bioscience Biomarkers and Research, Herlev, Denmark
Alexandar Tzankov
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
Peter Boor
Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
Mark P. Kühnel
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Institute of Pathology, Hannover Medical School, Hannover, Germany
Florian P. Länger
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Institute of Pathology, Hannover Medical School, Hannover, Germany
Stijn E. Verleden
Department of Thoracic Surgery, University Hospital Antwerp Edegem, Belgium
Hans M. Kvasnicka
Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Germany
Hans H. Kreipe
Institute of Pathology, Hannover Medical School, Hannover, Germany
Axel Haverich
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Germany
Stephen M. Black
Department of Cellular Biology and Pharmacology, Center for Translational Research, Florida International University, USA
Axel Walch
Nordic Bioscience Biomarkers and Research, Herlev, Denmark
Paul Tafforeau
European Synchrotron Radiation Facility, Grenoble, France
Peter D. Lee
Hannover Unified Biobank, Hannover Medical School, Hannover Medical School, Germany
Marius M. Hoeper
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Corresponding author at: Department of Respiratory Medicine, German Center of Lung Research (DZL), Hannover Medical School, Carl-Neuberg-Straβe 1, 30625 Hannover, Germany.
Tobias Welte
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
Benjamin Seeliger
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
Sascha David
Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland
Detlef Schuppan
Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
Steven J. Mentzer
Laboratory of Adaptive and Regenerative Biology, Harvard Medical School, Brigham & Women's Hospital, Boston, United States; Corresponding author at: Department of Respiratory Medicine, German Center of Lung Research (DZL), Hannover Medical School, Carl-Neuberg-Straβe 1, 30625 Hannover, Germany.
Danny D. Jonigk
Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany; Institute of Pathology, Hannover Medical School, Hannover, Germany
Summary: Background: COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9–20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. Methods: We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients’ hospitalization time. Findings: The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. Interpretation: Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. Funding: This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.
