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

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.

Anatomie multi-échelle par imagerie synchrotron de la vascularisation bronchique dans l’infection à SARS-CoV-2

Objet L’architecture capillaire et la circulation bronchique habituelle semble sensiblement modifiée dans le cadre des pneumopathies à SARS-CoV-2, associés à des thromboses multiples [1], [2]. L’imagerie en contraste de phase par source synchrotron (sPCI) permet d’étudier précisément l’ensemble des tissus organiques à une résolution microscopique et de façon non destructive. Le but de cette étude était de comparer l’anatomie vasculaire bronchique entre un poumon sain et un poumon de patients infectés par la COVID-19. Méthodes Trois poumons témoins ont été prélevés au Laboratoire d’Anatomie Des Alpes Françaises puis comparés à trois poumons de patients infectés par le SARS-CoV-2, provenant de la banque d’organe de l’Université Witten/Herdecke (Allemagne). Après préparation, les poumons ont été imagés au Synchrotron Européen de Grenoble à 26μm, 6μm et 2μm sans injection de produit de contraste [3]. La vascularisation a été étudiée sur les coupes tomodensitométriques 2D et sur les reconstructions tridimensionnelles, puis sur coupes histologiques et via des injections-corrosions. Le projet a été financé par la Chan Zuckerberg Initiative. Résultats La circulation bronchique, qui provient de l’aorte thoracique et des artères intercostales, est modifiée par le processus inflammatoire et hypoxique. L’étude de l’anatomie microscopique bronchique en sPCI a permis d’établir la présence de nombreuses d’anastomoses de moins de 50μm entre la circulation bronchique et l’artère lobulaire dans les poumons de patients infectés par la COVID-19, entraînant un shunt doit-gauche intra-pulmonaire. Par ailleurs, une angiogenèse anarchique majeure a été détectée au niveau des plexus alvéolaires des zones atteintes par l’infection, au dépend des artères intra-lobulaires, par rapport aux poumons témoins. Conclusion L’imagerie sPCI réalisée a permis la première visualisation tridimensionnelle d’un shunt bronchio-pulmonaire dans la COVID-19 ainsi que les phénomènes de néovascularisations excessives associés.

The Pathology of Severe COVID-19-Related Lung Damage.

BACKGROUND: The histomorphological changes of lung damage in severe coronavirus disease 2019 (COVID-19) have not yet been adequately characterized. In this article, we describe the sequence of pathological changes in COVID-19 and discuss the implications for approaches to treatment. METHODS: Standardized autopsies were performed on thirteen patients who had died of COVID-19. The findings were analyzed together with clinical data from the patients' medical records. RESULTS: Most (77%) of the deceased patients were men. Their median age at death was 78 years (range, 41-90). Most of them had major pre-existing chronic diseases, most commonly arterial hypertension. The autopsies revealed characteristic COVID-19-induced pathological changes in the lungs, which were regarded as the cause of death in most patients. The main histological finding was sequential alveolar damage, apparently due in large measure to focal capillary microthrombus formation. Alveolar damage leads to the death of the patient either directly or by the induction of pulmonary parenchymal fibrosis. Diffuse lung damage was seen exclusively in invasively ventilated patients. CONCLUSION: Autopsies are crucial for the systematic assessment of new diseases such as COVID-19: they provide a basis for further investigations of disease mechanisms and for the devising of potentially effective modes of treatment. The autopsy findings suggest that focal damage of the microvascular pulmonary circulation is a main mechanism of lethal lung disease due to the SARS-CoV-2 virus. It may also be a cause of persistent lung damage in patients who recover from severe COVID-19.