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

doi:10.1016/j.ebiom.2022.104296

The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling

EBioMedicine. 2022 Nov:85:104296. doi: 10.1016/j.ebiom.2022.104296. Epub 2022 Oct 4.

Authors

Maximilian Ackermann¹, Jan C Kamp², Christopher Werlein³, Claire L Walsh⁴, Helge Stark³, Verena Prade⁵, Rambabu Surabattula⁶, Willi L Wagner⁷, Catherine Disney⁸, Andrew J Bodey⁹, Thomas Illig¹⁰, Diana J Leeming¹¹, Morten A Karsdal¹², Alexandar Tzankov¹³, Peter Boor¹⁴, Mark P Kühnel³, Florian P Länger³, Stijn E Verleden¹⁵, Hans M Kvasnicka¹⁶, Hans H Kreipe¹⁷, Axel Haverich¹⁸, Stephen M Black¹⁹, Axel Walch¹², Paul Tafforeau²⁰, Peter D Lee¹¹, Marius M Hoeper²¹, Tobias Welte², Benjamin Seeliger², Sascha David²², Detlef Schuppan²³, Steven J Mentzer²⁴, Danny D Jonigk³

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Centre for Advanced Biomedical Imaging, University College London, UK.
⁵ Research Unit Analytical Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁶ Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
⁷ 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.
⁸ Department of Mechanical Engineering, University College London, UK.
⁹ Diamond Light Source, Oxfordshire, Oxford, UK.
¹⁰ 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.
¹¹ Hannover Unified Biobank, Hannover Medical School, Hannover Medical School, Germany.
¹² Nordic Bioscience Biomarkers and Research, Herlev, Denmark.
¹³ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
¹⁴ Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
¹⁵ Department of Thoracic Surgery, University Hospital Antwerp Edegem, Belgium.
¹⁶ Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Germany.
¹⁷ Institute of Pathology, Hannover Medical School, Hannover, Germany.
¹⁸ 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.
¹⁹ Department of Cellular Biology and Pharmacology, Center for Translational Research, Florida International University, USA.
²⁰ European Synchrotron Radiation Facility, Grenoble, France.
²¹ 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. Electronic address: hoeper.marius@mh-hannover.de.
²² Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland.
²³ 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.
²⁴ Laboratory of Adaptive and Regenerative Biology, Harvard Medical School, Brigham & Women's Hospital, Boston, United States.

Abstract

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.

Keywords: Biomarkers; COVID-19; Fibrogenesis; Intussusceptive angiogenesis.

MeSH terms

Biomarkers / analysis
COVID-19*
Fibrosis
Humans
Ischemia / pathology
Lung / diagnostic imaging
Lung / pathology
Lung Diseases, Interstitial* / pathology
Post-Acute COVID-19 Syndrome

Substances

Biomarkers

Abstract

MeSH terms

Substances

Grants and funding