UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Ackermann, M; Kamp, JC; Werlein, C; Walsh, CL; Stark, H; Prade, V; Surabattula, R; ... Jonigk, DD; + view all (2022) The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling. eBioMedicine , 85 , Article 104296. 10.1016/j.ebiom.2022.104296. Green open access

[thumbnail of 1-s2.0-S2352396422004789-main.pdf]
Preview
Text
1-s2.0-S2352396422004789-main.pdf - Published Version

Download (3MB) | Preview

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.

Type: Article
Title: The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ebiom.2022.104296
Publisher version: https://doi.org/10.1016/j.ebiom.2022.104296
Language: English
Additional information: © 2022 The Author(s). Published by Elsevier B.V. under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Biomarkers, COVID-19, Fibrogenesis, Intussusceptive angiogenesis
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Mechanical Engineering
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10158022
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item