Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: a global perspective

Abstract

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.

Fig. 1. Coronavirus structure, putative origin, phylogenetic tree and evolution of variants.

a | Genetic structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other representative human coronaviruses. The genome of each virus is ~30 kb long. The replicase is encoded in two long open reading frames (ORF1a and ORF1b). The genetic composition of the respective viruses differs chiefly in the 3′ third of the genome. SARS-CoV-2 has 79% nucleotide sequence identity with severe acute respiratory syndrome coronavirus (SARS-CoV), the virus that caused the SARS epidemic in 2003. Four coronaviruses circulate seasonally in the human population, usually causing mild upper respiratory tract infection: the representative virus Human coronavirus-229E (HCoV-229E) is depicted. Three coronaviruses are highly pathogenic in humans: SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV) cause infections with a fatality rate substantially greater than that of SARS-CoV-2; however, of these three viruses, SARS-CoV-2 transmits most efficiently between humans. b | Phylogenetic tree depicting the relatedness between SARS-CoV (from the 2003 SARS epidemic), SARS-CoV-2, and coronaviruses isolated from bats and civets. SARS-CoV-2 has ~97% nucleotide identity with the bat coronavirus RaTG13. c | Electron micrograph of a SARS-CoV-2 particle, covered in spike (S) proteins. d | Structure of a SARS-CoV-2 particle, showing the structural proteins of the virus. The particle has a diameter of ~125 nm. The trimerized S protein, which is the receptor-binding protein, gives the virion its crown-like appearance. The membrane (M) protein is the most abundant structural protein in the virus and seems to give the virus its shape. The third protein in the viral lipid envelope is the envelope (E) protein, which has ion channel activity and facilitates the assembly and release of the virion from the infected cell. The nucleoprotein (N) binds to the single-stranded RNA genome and regulates its structure and replication. The non-structural proteins are not illustrated. e | Structure of the S protein monomer. The surface that binds angiotensin-converting enzyme 2 (ACE2), the cellular receptor for the virus, is shown in green. Marked in yellow are the positions of three key mutations present in the SARS-CoV-2 virus variant B.1.351, which was first identified in South Africa. The N501Y mutation, which has evolved independently in different geographical locations, including the variant detected first in the UK (B.1.1.7), increases the affinity of binding of the (trimerized) S protein to the ACE2 receptor, resulting in greater transmissibility of the virus. Further mutations that increase the transmissibility of the virus have been identified in other variants of concern (Table 1). f | Immune responses to SARS-CoV-2 infection include the generation of interferons, natural killer cells, antibodies, and CD4⁺ and CD8⁺ T cells. The efficacy of the host immune response in the first week of infection is an important determinant of the risk of developing coronavirus disease 2019. SARS-CoV-2 encodes proteins that suppress the interferon response, resulting in efficient viral replication. UTR, untranslated region. Part a adapted with permission from refs^,, Elsevier and Springer Nature Ltd, respectively. Part b published with permission from M. Escalera Zamudio (University of Oxford, UK). Part c © National Infection Service/Science Photo Library.

Fig. 2. Global distribution of COVID-19 cases and deaths.

a | As of 24 August 2021, a total of 212,357,898 cases of coronavirus disease 2019 (COVID-19) have been confirmed. b | As of 24 August 2021, a total of 4,439,843 deaths have been reported to the WHO. Data from ref..

Fig. 3. Macrovascular changes in lungs from patients with severe COVID-19.

Pulmonary angiograms and dual-energy CT (DECT) scans in two patients with coronavirus disease 2019 (COVID-19) pneumonia without evidence of pulmonary emboli. a | Peripheral ground-glass opacities are present in the lower lobes (black arrowheads), and central ground-glass opacities are noted in the right middle and left lower lobes (white arrows). b | The corresponding DECT image shows a peripheral perfusion defect with a halo of increased perfusion in the left lower lobe (black arrows). Areas of increased perfusion corresponding to the central ground-glass opacities are also present (white arrowheads). c | Areas of peripheral ground-glass opacity are present in the posterior lungs (black arrowheads), and central ground-glass opacities with enlarged vessels are present in the upper lobes (white arrows). d | The corresponding DECT image shows peripheral areas of decreased perfusion with surrounding halos of increased perfusion (black arrows). Reproduced with permission from ref., Elsevier.

Fig. 4. Microvasculature changes in lungs from patients with severe COVID-19.

Haematoxylin and eosin (H&E) staining and immunostaining images showing microvasculature changes in patients with severe coronavirus disease 2019 (COVID-19). a | Arteriole filled with neutrophils that are in part adherent to the endothelium. b,c | Pulmonary microvessels (either arterioles or venules) displaying perivascular lymphocytic infiltrate. d | Immunostaining with anti-CD3 showing the vessel displayed in part c. e | Anti-CD4 staining on a serial section of the same vessel. f | Anti-CD8 staining on another serial section of the same vessel. g | Lymphocytic endothelialitis or venulitis with transmural infiltrate involving the intima; note the immediate vicinity of lymphocytes (dark blue, round nuclei) and endothelial cells (arrows). This inflammatory pattern is not frequently encountered and seems also to involve post-capillary vessels, as shown. h | Elastic-type artery (>500 μm in diameter) containing a wall-adherent, organized thrombotic lesion with endothelium-lined, cushion-like intimal fibrosis protruding into the vascular lumen.

Fig. 5. COVID-19-induced changes in cells of the lung vascular wall.

a | Mechanisms of endothelial injury in coronavirus disease 2019 (COVID-19). On the left is a histological image showing endothelial swelling (arrows). The cartoon on the right shows the mode of entry of severe acute respiratory syndrome coronavirus (SARS-CoV-2) via the angiotensin-converting enzyme 2 (ACE2) receptor, which induces endothelial apoptosis. To the right are scanning electron micrographs of microvascular corrosion casts from the thin-walled alveolar plexus of a healthy lung (upper left panel) and the substantial architectural distortion seen in lungs injured by COVID-19 (upper right panel). The loss of a clearly visible vessel hierarchy in the alveolar plexus is the result of new blood vessel formation by intussusceptive angiogenesis. The lower left panel shows the intussusceptive pillar localizations (arrowheads) at higher magnification. The lower right panel is a transmission electron micrograph showing ultrastructural features of endothelial cell destruction and SARS-CoV-2 visible within the cell membrane (arrowheads). Red cells (RCs) are labelled. b | Contribution of pericytes to vascular injury. The cartoon shows the different types of pericyte located along a vessel, from the arteriole to the venule. After infection with SARS-CoV-2, pericytes detach and undergo apoptosis, leading to increased microvascular permeability and cytokine storm. The electron microscopy images show the intimate association between pericytes (P) and endothelial cells in human lung capillaries. The pericytes are located within the basement membrane (B) and extend long, thin pericyte processes (PPs) that establish contacts with the adjacent endothelial cell. Also labelled are the alveolus (A), endoplasmic reticulum (er), endothelium (E) and cytoplasmic filament (F). The lower panel is a higher magnification of a section of the upper panel. c | Smooth muscle cells (SMCs). A histological image and cartoon showing de-differentiation and proliferation of SMCs in COVID-19, resulting in increased medial wall thickness and muscularization. d | Fibroblasts. A histological image and cartoon showing fibroblast proliferation and deposition of fibrin and extracellular matrix in COVID-19, resulting in adventitial thickening and parenchymal lung fibrosis (arrows). Micrographs in part a adapted with permission from ref., Massachusetts Medical Society. Cartoon of types of pericyte in part b adapted from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Micrographs in part b adapted with permission from ref., Wiley.

Fig. 6. Sequelae of acute COVID-19 infection.

a | Radiographic grading of lung fibrosis in a patient with coronavirus disease 2019 (COVID-19) and severe pulmonary fibrosis. (1) Chest high-resolution CT at discharge from hospital. (2) Extent of lesions marked in red using artificial intelligence (AI) at discharge from hospital. (3) Chest high-resolution CT at 30 days after discharge from hospital. (4) Extent of lesions marked in red using AI at 30 days after discharge from hospital, indicating a substantial reduction in lung fibrosis. b | Mechanisms of acute and chronic COVID-19-related pulmonary hypertension. Part a adapted from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Part b adapted from ref. (Springer Nature Ltd).

Fig. 7. Selected inflammatory pathways that are dysregulated in COVID-19.

Various inflammatory signalling pathways become dysregulated in patients with coronavirus disease 2019 (COVID-19). The figure shows the receptor-mediated transduction pathways from receptors to second messengers and ultimately to the nucleus and/or mitochondria. Targeting these pathways using selective anti-inflammatory drugs (pink boxes) might be therapeutically beneficial in patients with COVID-19. AAK1, AP2 associated protein kinase 1; ADAM17, a disintegrin and metalloproteinase 17; AP1, activator protein 1; ARB, angiotensin II receptor blocker; AT2R, angiotensin II receptor; COX2, cyclooxygenase 2; GHR, growth hormone receptor; ICAM, intercellular adhesion molecule; IFNγ, interferon-γ; JAK, Janus kinase; IκB, inhibitor of NF-κB; mTOR, mechanistic target of rapamycin; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MyD88, myeloid differentiation primary response protein MyD88; NF-κB, nuclear factor-κB; NSAID, non-steroidal anti-inflammatory drug; PI3K, phosphoinositol 3-kinase; PPAR, peroxisome proliferative activator receptor; RAF, RAF proto-oncogene serine/threonine-protein kinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STAT, signal transducer and activator of transcription; sTNF, soluble tumour necrosis factor; TAK1, nuclear receptor subfamily 2 group C member 2; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor; TLR, Toll-like receptor; TRADD, TNF receptor type 1-association DEATH domain protein; TRAF, TNF receptor-associated factor; TZD, thiazolidinedione; VCAM, vascular cell adhesion molecule. Adapted with permission from ref., Elsevier.

Fig. 8. COVID-19 with obliterating endothelialitis associated with complement activation and accumulation of C5aR1-expressing macrophages around vessels.

a | Haematoxylin and eosin staining of obliterating endothelialitis lesions in the lung of a representative patient with coronavirus disease 2019 (COVID-19). b | Representative multiplexed immunohistochemical staining of complement component 5a receptor 1 (C5aR1; green), CD68 (red) and CD163 (orange) showing that obliterating endothelialitis is associated with C5aR1⁺ macrophages surrounding the arteries and endothrombus (white dashed line). c | Hypothetical pathway for complement-mediated inflammation of the pulmonary alveolus in COVID-19. (1) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attaches to an angiotensin-converting enzyme 2 (ACE2) receptor on a type II alveolar epithelial cell (AEC-II), and the cell undergoes apoptosis. (2) Complement activation is initiated upon recognition of viral glycans by lectins (such as collectin 11 and ficolin 1, which are secreted by AEC-II) complexed with mannose-binding lectin-associated serine proteases (MASPs), including MASP2. Direct binding of MASP2 to the nucleoprotein of SARS-CoV-2 has also been suggested to initiate lectin pathway activation. (3) Complement deposition and membrane attack complex (MAC)–C5b-9 formation on AECs cause inflammasome activation and cell damage. (4) Release of complement C5a increases vascular permeability and recruitment/activation of polymorphonuclear leukocytes (PMNs) and monocytes to the alveolus. (5) Monocytes differentiated into inflammatory macrophages overproduce pro-inflammatory cytokines in response to C3a and C5a stimulation. (6) Endothelial cell (EC) activation by C5a and MAC predisposes to thrombus formation, which is further increased through mannose-binding lectin recognition of viral particles in the vascular compartment, leading to the cleavage of thrombin and fibrinogen by MASPs. Drugs that can target complement activation are shown in the pink boxes. DAMP, damage-associated molecular pattern; mAB, monoclonal antibody. Parts a and b adapted from ref., Springer Nature Ltd. Part c adapted from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).