key: cord-0930673-wua4agoz
authors: Brondani, Giovanni; Apollonio, Luca; Gremese, Elisa; Ferraccioli, Gianfranco
title: Pulmonary intravascular coagulopathy in COVID-19 pneumonia
date: 2020-06-29
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30189-2
sha: 010b0d190cf7e50c6c6f204a470d347d7af6c0a2
doc_id: 930673
cord_uid: wua4agoz

nan

We read with pleasure the thought ful Viewpoint by Dennis McGonagle and colleagues 1 on lung immunothrombosis during infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, some of the key pathogenetic events were not highlighted by the authors. Evidence from the early stages of disease suggest the occurrence of diffuse alveolar damage with infiltrating multinucleated cells and few macrophages. 2 CT perfusion scans done in patients with early pneumonitis reveal microangiopathy that presents as hypoperfusion of the involved parenchyma (appendix). McGonagle and colleagues cite a study in which single-cell analysis showed no angiotensin-converting enzyme 2 (ACE2) expression in endothelial cells or alveolar macrophages. 1 However, other studies showed ACE2 expression in vascular endo thelial cells in the lungs during infection with severe acute respiratory syndrome coronavirus (SARS-CoV), 3 or in the kidney during SARS-CoV-2 infection, 4 supporting the hypothesis that there is a receptor in all endo thelial cells at the systemic level.

By infecting endothelial cells, the virus could alter the cells' function from the inside, as happens for other viruses.

McGonagle and colleagues note that endothelial cells indeed express ACE2. The microangiopathy seen in patients with COVID-19 might therefore arise both from the inside (endothelial cells) and from the outside (platelets, cytokines, neutrophil extracellular traps, thrombophilic factors), resulting in, what we call endothelial leukothrombo-inflammation.

Alveolar haemorrhage can also occur in COVID-19 and an autopsy series from the USA showed foci of haemor rhage in all but one patient plus diffuse alveolar damage and mildto-moderate infiltrates of CD4+ and CD8+ lymphocytes; CD4+ T cells were seen in aggregates around small blood vessels, some of which appeared to contain platelets and small thrombi. In addition, fibrin thrombi were present within the capillaries and small blood vessels with entrapment of numerous neutrophils. Neutrophil extracellular traps have been observed in the advanced phases of lung inflammation and one preprint paper reported the presence of CD61+ megakaryocytes. 5 Since platelets are normally produced in the lung, the thrombotic events are certainly facilitated. However, it is crucial to recall the hierarchical role of endothelial cells, which appear to be central regulators of the cyto kine storm. In models of viral post-influenza inflammatory storms in the lung, triggering sphingosine-1-phosphate (S1P 1 ) receptors, which are expressed on endothelial cells and lympho cytes in the lung, sup pressed cytokine production, innate immune cell recruitment, and cyto kine release syndrome, 6 thereby decreasing lethality. Clinically, this finding could mean that, failing effective antiviral ther apy (eg, remdesivir), treatments aimed at suppressing cellular aggre gation or neutro phil extracellular trap forma tion and triggering S1P 1 signal ling (eg, fingolimod) could be crucial in curtail ing the endothelial leuko-thromboinflammatory storm before it starts, thus reducing the high mortality rate observed in patients with COVID-19 treated in intensive care units.

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Endothelial cell infection and endotheliitis in COVID-19

Vander Heide RS. Pulmonary and cardiac pathology in Covid-19: the first autopsy series from New Orleans

Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection