Time to move away from an oxygen-centric model of pulmonary infarction?

In their Series paper in The Lancet Respiratory Medicine, Dennis McGonagle and colleagues¹ propose a tricompartmental model of lung-oxygenation disruption to explain the increased incidence of pulmonary infarction in COVID-19. This model is based on the premise that hypoxia is the primary determinant of pulmonary infarction. While challenging this dogma, we share an alternative view of the mechanism of pulmonary infarction in COVID-19.

Pulmonary infarction occurs in about 30% of individuals with pulmonary arterial occlusion.² Although infarction is intuitively associated with hypoxic injury, lung tissue is distinct in this regard. The gas-exchange parenchyma, which comprises the majority of lung tissue, receives oxygen primarily from inspired air. Given that the principal role of pulmonary arterial flow is oxygen extraction rather than oxygen delivery, alveolar oxygen content would increase following pulmonary arterial occlusion. Therefore, it is highly unlikely that hypoxia is a major determinant of vaso-occlusive lung injury.

An alternative hypothesis³ of pulmonary infarction invokes compensatory bronchial arterial inflow at systemic pressures through bronchopulmonary anastomoses. This mechanism clarifies the paradoxical higher incidence of infarction after distal occlusion² and in people with high left-ventricular filling pressures. Unlike in proximal occlusion, in which the large pulmonary arterial bed can accommodate the abrupt influx of bronchial blood, small-vessel occlusion leads to alveolar haemorrhage and necrosis, because the inflow is greater than that which a small segment of pulmonary vasculature can accommodate. Further, this hypothesis clarifies the initial hyperaemia observed on radiology followed by rapid resolution (melting away) as tissue oedema resolves. These infarcts are considered to be incomplete because of the absence of tissue necrosis. The haemorrhagic necrosis seen in autopsies further corroborates this explanation. Crucially, this mechanism explains pulmonary infarction independent of oxygen supply.

Figure.

3D dual-energy CT pulmonary blood volume image from a patient with COVID-19, which shows multiple wedge-shaped pulmonary infarcts (green arrows)

In the context of COVID-19, several findings do not support tricompartmental disruption of oxygenation as primarily determining pulmonary infarction. First, subpleural ground-glass opacification (an initial sign of pulmonary infarction)¹ excludes severe alveolitis at the outset and indicates alveolar gas sufficient for alveolar-cell oxygenation. Second, bronchopulmonary anastomoses are demonstrable histopathologically⁴ and by positive-microbubble study,⁵ indicating the patency of terminal bronchial circulation.

The increased frequency and the inter-individual differences in vaso-occlusive lung injury in COVID-19 might be best explained as follows. First, because of distal-predominant vessel occlusion, compensatory bronchial arterial inflow results in marked tissue congestion. In some cases, this congestion resolves completely (incomplete pulmonary infarction), whereas in other cases it advances to haemorrhagic necrosis. Second, rather than hypoxia, oxidative stress probably contributes substantially to tissue infarction in COVID-19. Disruption of perfusion-dependent redox homoeostasis would exacerbate oxidative damage by macrophages, neutrophils undergoing NETosis, and free iron from disrupted erythrocytes.

We declare no competing interests. We thank Lynette Teo, Low Ting Ting, and Tung Moon Ley for their help with the acquisition, processing, and interpretation of the dual-energy CT image, and for the clinical care of the patient involved.