The primary life-limiting pulmonary morbidity of severe coronavirus disease (COVID-19) is characterized by pulmonary endothelialitis, microangiopathy, and aberrant angiogenesis (1). Although numerous studies have highlighted the pronounced microangiopathy in pulmonary circulation, the impact of the bronchial vascular system has not been fully elucidated. Therefore, we comprehensively analyzed complete lung lobes from three male patients (age, 63.7 ± 14.2 years; hospitalization time, 22 ± 1 days, mechanically ventilated) who succumbed to severe COVID-19 using conventional computed tomography, histology, microvascular corrosion casting, and hierarchical phase-contrast tomography (2). We used three control lungs from body donors (age, 78.3 ± 13.6 yr; nonventilated, two females and one male died from cerebral stroke or uterine carcinoma).
In pulmonary computed tomography angiography, we found the previously reported pulmonary sequelae of COVID-19 lung injury in the form of bilateral peripheral ground-glass opacities, peribronchial consolidations, and peripheral macrovascular congestion (3) (Figures 1A and 1B). Peribronchial and perivascular microvessels (vasa vasorum) were distinctly dilated (Figures 1C–1F). This intrapulmonary shunting by the bronchial circulation (Figure 2A) accounts for the continued perfusion in a variety of airway conditions, such as inflammation, acute respiratory distress syndrome, and chronic thromboembolism (3). In severe COVID-19 pneumonia, the microvascular architecture of the peribronchial vessels showed a microvascular architecture with densely packed aberrant bundles of blood vessels (Figures 2B–2E). The expansion of the peribronchial plexus is mainly driven by intussusceptive angiogenesis as evidenced by the appearance of transluminal endothelial tissue pillars (Figures 2B–2D) (1, 4, 5).
A spatial analysis of peribronchial vessels in COVID-19 pneumonia by hierarchical phase-contrast tomography demonstrated the expansion of peribronchial and perivascular arteriovenous anastomoses and a recruitment of “Sperrarterien” (blockade arteries) across individual secondary pulmonary lobules in the third dimension for the first time (Figures 3A and 3B and Video E1 in the online supplement). This intralobular shunting is accompanied by different spots of glomerouid-like vascular expansion (Figures 3C and 3D).
Here, we show the first insight into the complex three-dimensional phenomenon of bronchiopulmonary shunting in COVID-19. However, the sequelae of this excessive neovascularization, the actual remodeling that may account for intralesional hyperperfusion and long-term implications, have so far not been understood.
|1.||Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;383:120–128.|
|2.||Walsh C, Tafforeau P, Wagner WL, Jafree DJ, Bellier A, Werlein C, et al. Imaging intact human organs with local resolution of cellular structures using hierarchical phase-contrast tomography. Nat Methods [online ahead of print] 4 Nov 2021; DOI: 10.1038/s41592-021-01317-x.|
|3.||McCullagh A, Rosenthal M, Wanner A, Hurtado A, Padley S, Bush A. The bronchial circulation--worth a closer look: a review of the relationship between the bronchial vasculature and airway inflammation. Pediatr Pulmonol 2010;45:1–13.|
|4.||Eldridge L, Wagner EM. Angiogenesis in the lung. J Physiol 2019;597:1023–1032.|
|5.||Ackermann M, Mentzer SJ, Kolb M, Jonigk D. Inflammation and intussusceptive angiogenesis in COVID-19: everything in and out of flow. Eur Respir J 2020;56:2003147.|
Supported by NIH Grant HL94567 and NHLBI Grant HL134229 (M.A. and S.J.M.), an H2020 European Research Council Consolidator Grant XHale (771883, D.D.J.), Deutsche Forschungsgemeinschaft (Project Z2) Grant KFO311 (D.D.J.), Chan Zuckerberg Initiative Grant 2020-225394, an advised fund of Silicon Valley Community Foundation, the ESRF beamtime proposal md1252, Diamond Light Source (MG27025, MG27094), the Royal Academy of Engineering Grant CiET1819/10 (P.D.L.), and the MRC (MR/R025673/1). C.W. is supported by the MRC Skills Development Fellowship (MR/S007687/1). This work was also supported by the German Registry of COVID-19 Autopsies (DeRegCOVID), which is supported by the Federal Ministry of Health (ZMVI1-2520COR201), and the Federal Ministry of Education and Research as part of the Network of University Medicine (Bundesministerium für Bildung und Forschung DEFEAT PANDEMIcs, 01KX2021).
Author Contributions: M.A., W.L.W., C.W., S.J.M., and D.D.J. managed the patients. M.A., P.T., C.W., M.P.K., F.P.L., C.D., A.B., S.E.V., and D.D.J. worked up surgical specimens. M.A., P.T., W.L.W., C.L.W., C.W., M.P.K., C.D., A.J.B., A.B., S.E.V., P.D.L., S.J.M., and D.D.J. interpreted the data. M.A., S.E.V., S.J.M., and D.D.J. wrote the manuscript. M.A., P.T., C.W., M.P.K., C.D., A.B., S.E.V., and D.D.J. prepared the images. M.A., P.T., W.L.W., C.L.W., C.W., M.P.K., F.P.L., C.D., A.B., S.E.V., P.D.L., S.J.M., and D.D.J. revised the manuscript.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202103-0594IM on August 31, 2021