COVID-19 Lung Damage Is More Than Pneumonia
A new study offers information on the unique pathology suffered by COVID-19 patients and on the extent of viral replication in their lungs.
These researchers state: ‘COVID-19 is a unique disease characterized by extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, along with the presence of infected cell syncytia.’
Published by The Lancet on November 3, 2020, these researchers stated: ‘It has been suggested that COVID-19 follows a biphasic course, with an initial phase characterized by viral replication, also detectable by positivity at the RT-PCR-based swab test, followed by second phase in which viral replication might become less relevant, characterized by hyperinflammation.’
While the clinical manifestations of the disease remain different during disease progression, our data challenge the notion that viral replication has ceased in patients with advanced disease.
The patients who died after prolonged intensive care in this study, alveolar damage was found to be massive, as previous studies have also revealed.
In light of the persistence of virus-infected cells in the lungs of infected individuals and the peculiar molecular features of the SARS-CoV-2 Spike protein we propose that several of the clinical characteristics that set COVID-19 apart from other interstitial pneumonias are not attributable to pneumocyte death as a consequence viral replication, but to the persistence of virus-infected, Spike-expressing cells in the lungs of the infected individuals.’
This in situ RNA hybridization for the detection of the SARS-CoV-2 genome univocally indicates that the alterations in the lung are concomitant with persistent viral infection of pneumocytes and endothelial cells. RNA-positive pneumocytes were largely present in the lungs of 10/11 tested individuals.
The damage to the lungs was not dissimilar from that of patients succumbing from acute respiratory distress syndrome (ARDS) secondary to other conditions, and included detachment of alveolar pneumocytes, deposition of hyaline membranes and marked interstitial edema with advanced fibrotic organization, which are characteristics of advanced Diffuse alveolar damage (DAD) from different causes including SARS-1.
In addition to persistent viral infection, at least two additional hallmarks characterize the COVID-19 pathology.
First, the presence of massive lung thrombosis. This was evident at the macroscopic examination in 5/6 patients from IC Unit and in 31/41 patients analyzed at the histological level.
Fibrin deposition and thrombosis affected both small and large pulmonary vessels and showed clear signs of heterochronicity, with several fresh thrombi neighboring thrombi in advanced stage of organization.
This is indicative of a pro-thrombotic process ongoing in the lungs rather than an embolic dissemination event. In terms of defining the underlying cause for thrombosis, we found several endothelial cells lining small and larger vessels infected with the virus.
Infection of endothelial cells is rendered possible by the known expression of the ACE2 receptor in these cells. Endothelial cells expression of activation markers, such as VCAM-1 and E-Selectin, and of dysfunctional markers such as Tissue Factor are not specific of COVID-19, as these can be found in other inflammatory and infectious conditions.
However, it is tempting to speculate that the extent of these alterations, the concomitant frequent detection of virus-positive endothelial cells and the high rate of thrombosis of COVID-19 patients might be causally related.
In addition to persistent viral infection, endothelial dysfunction and lung thrombosis, this study indicates that a third hallmark of COVID-19 disease is the presence of large numbers of dysmorphic cells in the lung.
Presence of abnormal pneumocytes and syncytial giant cells is also detected in other conditions of DAD, however in a more sporadic and occasional manner.
Additionally, most giant cells in other conditions, including SARS-1, appear to be of histiocytic origin and are not infected by SARS-CoV-2, suggesting they derive from the host inflammatory response.
We attribute the high prevalence of these syncytial cells to the properties of the SARS-CoV-2 Spike protein. Both SARS-1 and SARS-CoV-2 bind the ACE2 receptor and can be activated by the TMPRSS2 protease.
However, in the case of SARS-CoV, a main route for Spike activation follows endocytosis of the viral particles and is carried out by endosomal, low pH-activated proteases such as cathepsin B and cathepsin L.
In contrast, other proteases, in particular furin, can prime SARS-CoV-2 Spike directly at the plasma membrane level, targeting a sequence at the S1/S2 interface that is not present in SARS-1.
As a consequence, cells expressing SARS-CoV-2 Spike can fuse with other cells expressing the ACE2 receptors and form syncytia, while this property is less pronounced for Spike from SARS-1. The possible pathogenetic significance of this difference has remained so far unexplored.
Besides the lung, we could not detect overt signs of possible viral replication in other organs, including brain, liver, heart and kidney. This does not exclude, however, that infection of a very few cells in these organs, which have escaped our morphological analysis, would still be a cause for disease.
This observation might hint at the possibility that the fusogenic properties of the MERS-CoV- and SARS-CoV-2-infected cells might be linked to the pathogenesis of thrombosis. Further investigations are needed in this respect, concluded these researchers.
This work was supported by a King's Together Rapid COVID-19 Call grant from King's College London. MG is supported by the European Research Council (ERC) Advanced Grant 787971 “CuRE” and by Programme Grant RG/19/11/34633 from the British Heart Foundation.
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