A tricompartmental model of lung oxygenation disruption to explain pulmonary and systemic pathology in severe COVID-19

Abstract

The emergent 21st century betacoronaviruses, including SARS-CoV-2, lead to clinicopathological manifestations with unusual features, such as early-onset chest pain, pulmonary infarction, and pulmonary and systemic thromboembolism that is pathologically linked to extensive capillary, arteriolar, and venular thrombosis. Early ground glass opacities detected by CT, which are reminiscent of lung infarcts associated with pulmonary embolism, point to a novel vascular pathology in COVID-19. Under physiological conditions, normal parenchymal oxygenation is maintained by three sources: the alveolus itself and dual oxygen supply from the pulmonary and bronchial artery circulations. We propose a model in which these three components are disrupted in COVID-19 pneumonia, with severe viral alveolitis and concomitant immunothrombotic obstruction of the pulmonary and bronchiolar circulation. Tricompartmental disruption might have two main consequences: systemic clot embolisation from pulmonary vein territory immunothrombosis, and alveolar-capillary barrier disruption with systemic access of thrombogenic viral material. Our model encompasses the known pathological and clinical features of severe COVID-19, and has implications for understanding patient responses to immunomodulatory therapies, which might exert an anti-inflammatory effect within the vascular compartments.

Figure 1

Pulmonary arterial filling defects in severe COVID-19 (A) Typical pulmonary emboli originating from the deep venous circulation, detected by CT pulmonary angiogram, are larger, fewer in number, and more central than those reported in severe COVID-19. Pulmonary emboli described in severe COVID-19 might be linked, at least in part, to conventional risk factors. (B) Pulmonary intravascular coagulopathy is a type of inflammation-driven immunothrombosis that arises due to the extensive interface between alveoli and the capillary network, manifesting as distal pulmonary artery and vein branch occlusion in COVID-19. We propose that extensive small vessel arteriolar inflammation and immunothrombotic occlusion could lead to retrograde extension, manifesting as multiple distal emboli (actually thrombi) supplying areas of pneumonic consolidation. Distal territory infarction might contribute to pleuritic chest pain with a negative CT pulmonary angiogram (thrombi are beyond the resolution capability of CT). (C) Coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 show proclivity to alveolar pneumocyte infection and damage. Severe viral alveolitis is associated with immunothrombosis of the integrated arteriolar, capillary, and venular networks adjacent to sites of extensive viral alveolitis or extensive immune activation in response to alveolitis. By contrast, RSV and influenza show a more bronchiole-centric infection that is proximal to the alveolar network and cause damage without the same degree of insult to the alveolar capillary network. DVT=deep vein thrombosis. MERS-CoV=Middle East respiratory syndrome coronavirus. RSV=respiratory syncytial virus. SARS-CoV=severe acute respiratory syndrome coronavirus.

Figure 2

A tricompartmental model of severe COVID-19 The three oxygen inputs to the lung are compromised in COVID-19: direct alveolar oxygenation; the pulmonary circulation comprising arteriolar, capillary, and pulmonary venular territory; and the bronchial artery circulation. (A) SARS-CoV-2 infection leads to severe alveolitis, which restricts the direct oxygen supply in COVID-19 pneumonia. (B) Immunothrombosis disrupts the alveolar capillary network and the terminal pulmonary arterioles (one of the dual blood supplies). Stasis within multiple pulmonary arteriolar vessels, with retrograde clot extension into larger pulmonary arteries, can be detected on CT pulmonary angiogram. The second blood supply, from the bronchial artery (which is known to terminate at the level of terminal bronchioles, where it anastomoses with pulmonary capillaries and venules) is also disrupted and is key to understanding why pulmonary infarction occurs, because it transmits oxygenated blood to the alveolus, unlike the pulmonary artery, in which blood is deoxygenated. Pulmonary infarction in COVID-19 also arises from pulmonary venular territory thrombosis caused by stasis of the pulmonary and bronchial circulations, and the inflammatory response within the circulation and the closely juxtaposed extra-venular alveolar networks. The vascular compartment is strongly linked to immune-driven thrombosis rather than direct viral infection.

Figure 3

Tricompartmental dysregulation and the severe systemic impact of COVID-19 (A) Immunothrombosis disrupts the terminal pulmonary arterioles (one of the dual blood supplies) and also eliminates anastomoses between the small bronchial artery and the distal pulmonary arteriole or capillary and vein, eliminating the wash-through effect of the pulmonary venules by the bronchial artery, which maintains venous patency in pulmonary embolism. Clot formation within pulmonary venules that are distal to the capillary networks provides a source from which systemic embolisation can occur. (B) Breakdown of the alveolar–capillary barrier permits direct systemic circulation access to viral RNA (RNAaemia), viral proteins, and whole SARS-CoV-2 with the effect that the immunothrombotic process initially confined to the lung now becomes systemic, compounded by other independent factors including hypercoagulability and severe systemic immune activation of neutrophils, platelets, and mononuclear cells. Thus, failure of the tricompartmental model to constrain SARS-CoV-2 locally might lead to similar immunothrombotic complications in organs distant from the lung.