Ackermann, M

Bellier, A

Bodey, AJ

Disney, C

Jonigk, DD

Kühnel, MP

Lee, PD

Länger, FP

Mentzer, SJ

Tafforeau, P

Verleden, SE

Wagner, WL

Walsh, C

Werlein, C

English

UCL Discovery

IMAGES IN PULMONARY,CRITICAL CARE, SLEEP MEDICINEAND THE SCIENCESThe Bronchial Circulation in COVID-19 PneumoniaMaximilian Ackermann1,2, Paul Tafforeau3, Willi L. Wagner4, Claire L. Walsh5, Christopher Werlein6,7,Mark P. K€uhnel6,7, Florian P. L€anger6,7, Catherine Disney8, Andrew J. Bodey9, Alexandre Bellier10,Stijn E. Verleden11, Peter D. Lee8, Steven J. Mentzer12, and Danny D. Jonigk6,71Institute of Pathology andMolecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Witten, Germany;2Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg–University Mainz, Mainz, Germany;3European Synchrotron Radiation Facility, Grenoble, France; 4Department of Diagnostic and Interventional Radiology, GermanyTranslational Lung Research Center Heidelberg, German Lung Research Centre and University Hospital Heidelberg, Heidelberg,Germany; 5Centre for Advanced Biomedical Imaging and 8Department of Mechanical Engineering, University College London,London, United Kingdom; 6Institute of Pathology, Hannover Medical School, Hannover, Germany; 7Member of the German Center forLung Research, Biomedical Research in Endstage andObstructive Lung Disease Hannover, Hannover, Germany; 9DiamondLight Source, Oxfordshire, Oxford, United Kingdom; 10French Alps Laboratory of Anatomy, Grenoble Alpes University, Grenoble,France; 11Department of Thoracic and Vascular Surgery & Pneumology, University Hospital Antwerp, Antwerp, Belgium; and12Laboratory of Adaptive and Regenerative Biology, Harvard Medical School, Brigham andWomen’s Hospital, Boston, MassachusettsORCID ID: 0000-0001-9996-2477 (M.A.).The primary life-limiting pulmonary morbidity of severe coronavirus disease (COVID-19) is characterized by pulmonaryendothelialitis, microangiopathy, and aberrant angiogenesis (1). Although numerous studies have highlighted the pronouncedmicroangiopathy in pulmonary circulation, the impact of the bronchial vascular system has not been fully elucidated. Therefore, wecomprehensively analyzed complete lung lobes from three male patients (age, 63.76 14.2 years; hospitalization time, 226 1 days,mechanically ventilated) who succumbed to severe COVID-19 using conventional computed tomography, histology, microvascularcorrosion casting, and hierarchical phase-contrast tomography (2). We used three control lungs from body donors (age,78.36 13.6 yr; nonventilated, two females and onemale died from cerebral stroke or uterine carcinoma).In pulmonary computed tomography angiography, we found the previously reported pulmonary sequelae of COVID-19 lunginjury in the form of bilateral peripheral ground-glass opacities, peribronchial consolidations, and peripheral macrovascularcongestion (3) (Figures 1A and 1B). Peribronchial and perivascular microvessels (vasa vasorum) were distinctly dilated (Figures1C–1F). This intrapulmonary shunting by the bronchial circulation (Figure 2A) accounts for the continued perfusion in a varietyof airway conditions, such as inflammation, acute respiratory distress syndrome, and chronic thromboembolism (3). In severeCOVID-19 pneumonia, the microvascular architecture of the peribronchial vessels showed a microvascular architecture withdensely packed aberrant bundles of blood vessels (Figures 2B–2E). The expansion of the peribronchial plexus is mainly driven byintussusceptive 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 demonstratedthe expansion of peribronchial and perivascular arteriovenous anastomoses and a recruitment of “Sperrarterien” (blockadearteries) across individual secondary pulmonary lobules in the third dimension for the first time (Figures 3A and 3B and Video E1 inThis article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0.For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).Supported by NIH Grant HL94567 and NHLBI Grant HL134229 (M.A. and S.J.M.), an H2020 European Research Council Consolidator GrantXHale (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 SkillsDevelopment Fellowship (MR/S007687/1). This work was also supported by the German Registry of COVID-19 Autopsies (DeRegCOVID), whichis supported by the Federal Ministry of Health (ZMVI1-2520COR201), and the Federal Ministry of Education and Research as part of theNetwork of University Medicine (Bundesministerium f€ur 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., andD.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. interpretedthe 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.Am J Respir Crit Care Med Vol 205, Iss 1, pp 121–125, Jan 1, 2022Copyright © 2022 by the American Thoracic SocietyOriginally Published in Press as DOI: 10.1164/rccm.202103-0594IM on August 31, 2021Internet address: www:atsjournals:orgImages in Pulmonary, Critical Care, Sleep Medicine and the Sciences 121 FA BC DbradbrvsvsbrbrvsEFigure 1. Bronchial artery and vasa vasorum dilatation and expansion in coronavirus disease (COVID-19) pneumonia. (A) Dual energycomputed tomography revealed the characteristic features of severe COVID-19 pneumonia as bilateral ground-glass opacities, peribronchialconsolidations, and a diffuse crazy-paving pattern. (B) Iodine map showed dilatation of macrovessels in or leading to opacified air spaces andfrequently evident vascular “tree-in-bud” (blue arrows). (C and D) Hierarchical phase-contrast tomography (high-resolution tomographic imagesanalyzed by Synchrotron radiation X-ray tomographic microscopy) demonstrated the regular architecture in healthy control lungs (C), whereas inCOVID-19 pneumonia, a dilatation and an expansion of vasa vasorum and peribronchial vessels was observed (D). Scale bars: C, 1,000 mm;D, 400 mm. (E and F) Representative hematoxylin and eosin–stained sections show sporadic peribronchial vessels (black arrow) in the controltissue (E), whereas the peribronchial plexus in COVID-19 lungs was characterized by an expansion and the formation of angiomatoid- andplexiform-like vessels (black arrows) (F). Scale bars: 20 mm. ad=alveolar duct; br =bronchus; vs=pulmonary vessel.IMAGES IN PULMONARY, CRITICAL CARE, SLEEP MEDICINE AND THE SCIENCES122 American Journal of Respiratory and Critical Care Medicine Volume 205 Number 1 | January 1 2022 regular lung vascularity COVID-19 vascularityBDECAbrpa sa30% pleurohilar veins70% peripherallungSperrarterien312microthrombibronchial circulationpulmonary circulationbronchusCOVID-19 pneumoniaFigure 2. Intrapulmonary shunting via bronchial circulation in coronavirus disease (COVID-19) pneumonia. (A) The schematic illustratesintrapulmonary cross-circulation and draining by bronchial arteries to the peripheral lung, pleurohilar veins, and “Sperrarterien,” specialized,spiral-like intrapulmonary arteriovenous anastomoses recruited by hypoxia and flow irregularities. The bronchial circulation arises primarily directfrom the thoracic aorta and intercostal arteries and, under normal conditions, constitutes less than 2% volume of the left cardiac output.However, the bronchial flow can significantly exceed the regular hemodynamics upon hypoxic and inflammatory stimulus. As part of aphysiological right–left shunting, nearly two-thirds of the bronchial vessels are drained peribronchially to the peripheral lung and finally into theleft ventricle (up to 4% of left ventricular output), whereas the remaining third is perfused pleurohilar veins draining ultimately to the right heart.(B) Scanning electron micrograph of a microvascular corrosion cast demonstrates the expansion of vasa vasorum of an intralobular artery byintussusceptive angiogenesis (red arrowheads) in the lung tissue of a patient who succumbed to severe COVID-19 pneumonia. Scale bar,IMAGES IN PULMONARY, CRITICAL CARE, SLEEP MEDICINE AND THE SCIENCESImages in Pulmonary, Critical Care, Sleep Medicine and the Sciences 123 Figure 2. (Continued). 50 mm. Intussusceptive angiogenesis is a well-characterized morphogenetic process observed during the capillaryexpansion in cancer, inflammation, and regeneration, but it has also been reported in the alveolar plexus of COVID-19 lungs. Scale bar,100 mm. (C) Scanning electron micrograph of a microvascular corrosion cast demonstrates the peribronchial plexus in healthy control lungs(blue arrows). Scale bar, 200 mm. (D) Scanning electron micrograph of a microvascular corrosion cast reveals the cross-circulation in COVID-19lung tissue between a Sperrarterie and a lobular artery in a secondary pulmonary lobule, which is characterized by plexiform-like vascularproliferations by intussusceptive angiogenesis (red arrowheads). Scale bar, 200 mm. (E) Three-dimensional evaluation of microvascularcorrosion casts by Synchrotron radiation X-ray tomographic microscopy illustrating the irregular, hierarchical vascularity with dilated, blunt-likevessels in COVID-19 pneumonia. Scale bar, 100 mm. br =bronchiole, pa= lobular artery; sa=Sperrarterie.DCA BFEFigure 3. Three-dimensional complexity of vascular remodeling and bronchiopulmonary shunting in coronavirus disease (COVID-19) highlightedby hierarchical phase-contrast tomography. (A) The distal bronchiole (blue) is paralleled by a centrilobular pulmonary artery (red) and anexpanded plexus of private vessels (vasa vasorum) (yellow) in a secondary pulmonary lobule in the periphery of the left lower lobe. Scale bar,4 mm. (B) Dilatation and expansion of the peribronchiolar plexus and vasa vasorum (yellow) is observed around the distal terminal bronchiole(blue) and centrilobular pulmonary artery (red). Scale bar, 1.3 mm. (C) Numerous arteriovenous anastomoses (yellow) form between bronchialarteries and pulmonary artery drain into a pulmonary vein accompanied by a pronounced shunting of a Sperrarterie (white arrows). Thesespecialized arteries are essential for intrapulmonary arteriovenous shunting and are located mainly at the septal margin of secondary pulmonarylobules, where up to 3 to 5 such “Sperrarterien” anastomoses can be found in each lobule. Scale bar, 0.7 mm. (D) The perivascular vasavasorum and bronchial vascular plexus are characterized by complex nodular lesions with angiomatoid- and plexiform-like arrangements (whitearrowheads). Scale bar, 0.7 mm. For high-resolution details, see COVID-19 Pneumonia in the online supplement . (E) In controls, the vasculararchitecture shows a well-organized hierarchy of peribronchial vessels. Scale bar, 1.3 mm. (F) Only few perivascular vasa vasorum areobserved in healthy control tissue. Scale bar, 0.7 mm. For high-resolution details, see Control in the online supplement.IMAGES IN PULMONARY, CRITICAL CARE, SLEEP MEDICINE AND THE SCIENCES124 American Journal of Respiratory and Critical Care Medicine Volume 205 Number 1 | January 1 2022 the online supplement). This intralobular shunting is accompanied by different spots of glomerouid-like vascular expansion (Figures3C 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 intralesionalhyperperfusion and long-term implications, have so far not been understood.Author disclosures are available with the text of this article at www.atsjournals.org.References1. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T,Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, andangiogenesis 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 structuresusing hierarchical phase-contrast tomography. Nat Methods [onlineahead 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. Thebronchial circulation–worth a closer look: a review of the relationshipbetween the bronchial vasculature and airway inflammation. PediatrPulmonol 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. Inflammationand intussusceptive angiogenesis in COVID-19: everythingin and out of flow. Eur Respir J 2020;56:2003147.IMAGES IN PULMONARY, CRITICAL CARE, SLEEP MEDICINE AND THE SCIENCESImages in Pulmonary, Critical Care, Sleep Medicine and the Sciences 125 

The Bronchial Circulation in COVID-19 Pneumonia

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The Bronchial Circulation in COVID-19 Pneumonia

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