key: cord-0968186-0hm1shoh
authors: McGonagle, Dennis; O'Donnell, James S; Sharif, Kassem; Emery, Paul; Bridgewood, Charles
title: Pulmonary intravascular coagulopathy in COVID-19 pneumonia – Authors' reply
date: 2020-06-29
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30174-0
sha: 3e701276929543995414f1c136436fe462eacb27
doc_id: 968186
cord_uid: 0hm1shoh

nan

We thank Gianfranco Ferraccioli and colleagues, Brandon Reines and col leagues, and Hisyovi Cárdenas Suri for their comments on our Viewpoint 1 discussing the diffuse, alveolarcentred inflammation that triggers immu no thrombosis in the lung micro vasculature of patients with COVID19 pneumonia.

Ferraccioli and colleagues posit the role of severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection of angiotensinconverting enzyme 2 (ACE2)expressing endo thelial cells in driving this immu no thrombosis and other sys temic COVID19 manifestations, includ ing cardiac, neurological, and occa sional cutaneous features. It is worth noting that other respiratory viral infec tions, including severe acute respir atory syndrome, resulted in a similarly high degree of pulmonary intravascular coagulopathy. 2 Since there is no compelling evidence of cardiac endothelial damage, we favour the pulmonary intravascular coagulopathy model, particularly as thrombosis is predominantly observed within the lungs. Nevertheless, ACE2 expression on endothelial cells, detection of SARSCoV2 in the endothelium by electron microscopy, juxtaposition of infected alveoli, and reported circulatory viral RNAaemia support the impor tance of endothelium in pulmonary intravascular coagulopathy. Ferraccioli and colleagues further highlight the pivotal role of endothelium in experimental murine influenza, and that use of a sphingosine1phosphate agonist improved survival. However, we can point to other influenza murine models in which similar therapies worsened survival. 3 We also note the comments on neutrophil extracellular trap forma tion, or NETosis, and pulmonary vasculature megakaryocytes as poten tial contributors to pulmonary throm bosis. These factors might indeed be important but they do not detract from our central concept of pulmonary intravascular coagulopathy driven by initial infection of ACE2expressing pneumocytes in SARSCoV2 infection.

Reines and colleagues argue for a new conceptual framework to understand COVID19 disease and believe that use of the term diffuse is incorrect. We used this term to reflect the extensive and widespread lung involvement typically seen in patients with severe COVID19. Given the large surface area of the lungs, together with the close juxtaposition of endo thelium to pneu mocytes, a vast territory for triggering immunothrombosis exists. We acknowledge that other patho logical factors, including those relating to type 2 pneumocyte and surfactant biology, might contribute to the disease pathophysiology but these considerations are beyond the remit of our Viewpoint, which is to highlight how a pulmonary intravascular coagu lo pathy with secondary pulmonary hypertension accounts for mortality in some groups. As indicated in our Viewpoint and previous publications, 4 it seems highly probable that mul tiple mechanisms contribute to the pulmonary intravascular coagulo pathy, which clearly diverges from the classic macrophage activation syn drome pattern typically observed in rheumatology practice.

Hisyovi Cárdenas Suri points out that critically ill patients with COVID19 might actually be developing a catas trophic antiphospholipid antibody syndrome and that antiphospho lipid antibodies should be checked in an effort to improve the manag ement of these patients. In a cohort of 56 patients, 25 (45%) were reported to be positive for lupus anticoagulant. 5 Crucially, however, whether these anti phospholipid antibodies are transient or persistent in nature, or whether they play any pathological role in the development of thrombi within the lung microvasculature, is not known at this stage. Pending the results of further studies to address these key questions, we consider it premature to impli cate catastrophic antiphospholipid antibody syn drome in the aetiology underpinning pulmonary intravascular coagulopathy in severe COVID19.

Immune mechanisms of pulmonary intravascular coagulopathy in COVID19 pneumonia

Pulmonary pathology of severe acute respiratory syndrome in Toronto

FTY720 impairs CD8 Tcell function independently of the sphingosine1phosphate pathway

The role of cytokines including interleukin6 in COVID19 induced pneumonia and macrophage activation syndromelike disease

Lupus anticoagulant is frequent in patients with COVID19