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The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling.
EBioMedicine 85:104296 (2022)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Biomarkers ; Covid-19 ; Fibrogenesis ; Intussusceptive Angiogenesis
ISSN (print) / ISBN
2352-3964
e-ISSN
2352-3964
Journal
EBioMedicine
Quellenangaben
Volume: 85,
Article Number: 104296
Publisher
Elsevier
Publishing Place
Amsterdam [u.a.]
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Analytical Pathology (AAP)
Grants
Botnar Research Centre for Child Health, University of Basel
Medizinischen Hochschule Hannover
Deutsche Forschungsgemeinschaft
Chan Zuckerberg Initiative
UK-MRC
NATON
Federal Ministry of Health and Federal Ministry of Education and Research
Chan Zuckerberg Initiative Foundation
Medizinischen Hochschule Hannover
Deutsche Forschungsgemeinschaft
Chan Zuckerberg Initiative
UK-MRC
NATON
Federal Ministry of Health and Federal Ministry of Education and Research
Chan Zuckerberg Initiative Foundation