Transpulmonary Bubble Transit in Severe COVID-19: Pulmonary Vasodilatation or Angiogenesis?

To the Editor:

We read with great interest the recent publication in the Journal by Reynolds and colleagues describing pulmonary vascular dilatation as the cause of hypoxemia in coronavirus disease (COVID-19)–associated acute respiratory distress syndrome (ARDS) (1). The authors should be commended for this important contribution. The authors correctly point out that in order for transpulmonary bubble transit to occur, pulmonary vascular dilatations or pulmonary arteriovenous malformations must be present. We wish to further contribute by proposing an alternative cause of transpulmonary bubble transit in ARDS due to COVID-19. Ackermann and colleagues have recently described that lungs from patients with severe COVID-19 and ARDS exhibited a combination of 1) a more widespread intussusceptive angiogenesis characterized by intravascular pillar formation spanning the interior lumen of a capillary, resulting in generation of two daughter vessels, and 2) a sprouting angiogenesis by endothelial proliferation (2). The degree of intussusceptive angiogenesis was found to increase significantly with increasing duration of hospitalization (P < 0.001), whereas the lungs from patients with influenza had less intussusceptive angiogenesis and no increase over time (2).

As reviewed by Kolte and colleagues in 2016, intussusceptive angiogenesis is known to be highly dependent on flow alterations and hemodynamic forces, with vasodilation-induced change in shear stress inducing pillar formation (3). Apart from blood flow and hemodynamic forces, intussusceptive angiogenesis is also regulated by molecular factors (3). FGF2 (fibroblast growth factor 2) stimulates intussusceptive angiogenesis by inducing PDGFB (platelet-derived growth factor B)–responsive upregulation of PDGF receptors (3). Overexpression of VEGF (vascular endothelial growth factor) is associated with sprouting angiogenesis and increased vascular permeability, but the response to VEGF (sprouting vs. intussusceptive) may depend on the amount of VEGF expression, the release modality (slow vs. rapid liberation), and/or the differential expression of VEGF receptors (3). Tie-2 and Ang-1 also play an important role in intussusceptive angiogenesis. Overexpression of Ang-1 or of Ang-1 in combination with VEGF leads to the formation of enlarged vessels with abundant small invaginations in the capillary plexus that are reminiscent of transcapillary pillars encountered during intussusceptive angiogenesis (3).

Among angiogenesis-related genes, FGF2 and VEGFC genes were found to be upregulated in lungs from patients who died of COVID-19 but not in those with influenza A (H1N1) (2). VEGF-induced endothelial proliferation without tip-cell formation caused an initial homogeneous enlargement of preexisting microvessels, which was followed by the formation of intravascular transluminal pillars, hallmarks of intussusception (4). This was associated with increased flow and shear stress, which are potent triggers of intussusception (4). A similar process of enlargement without sprouting followed by intussusception is induced by VEGF overexpression (4).

Therefore, transpulmonary bubble transit, as reported by Reynolds and colleagues, may be caused either by 1) pulmonary vasodilatation, as proposed by the authors, or 2) intussusceptive and sprouting angiogenesis. On the other hand, pulmonary vasodilatation may serve as a stimulus for intussusceptive angiogenesis in severe COVID-19. The endothelial damage may progress through different stages of development in different areas of the lungs as time elapses from the initial injury (2). Therefore, although some areas of the lungs may exhibit pulmonary vascular dilatation, other areas may have progressed to intussusceptive or sprouting angiogenesis. Nitric oxide has been implicated in the pathogenesis of COVID-19, and it is notable that nitric oxide–induced arteriolar vasodilatation precedes development of intussusceptive angiogenesis (5). Understanding the mechanism underlying transpulmonary bubble transit observed by Reynolds and colleagues in severe COVID-19 (that is, pulmonary vascular dilatation, angiogenesis, or both) is of fundamental importance in designing and testing therapeutic strategies for this enigmatic disease.