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. 2022 Oct;12(10):a041157. doi: 10.1101/cshperspect.a041157

Endothelialitis, Microischemia, and Intussusceptive Angiogenesis in COVID-19

Steven J Mentzer 1, Maximilian Ackermann 2, Danny Jonigk 3
PMCID: PMC9524390  PMID: 35534210

Abstract

COVID-19 has been associated with a range of illness severity—from minimal symptoms to life-threatening multisystem organ failure. The severe forms of COVID-19 appear to be associated with an angiocentric or vascular phase of the disease. In studying autopsy patients succumbing to COVID-19, we found alveolar capillary microthrombi were 9 times more common in COVID-19 than in comparable patients with influenza. Corrosion casting of the COVID-19 microcirculation has revealed microvascular distortion, enhanced bronchial circulation, and striking increases in intussusceptive angiogenesis. In patients with severe COVID-19, endothelial cells commonly demonstrate significant ultrastructural injury. High-resolution imaging suggests that microcirculation perturbations are linked to ischemic changes in microanatomic compartments of the lung (secondary lobules). NanoString profiling of these regions has confirmed a transcriptional signature compatible with microischemia. We conclude that irreversible tissue ischemia provides an explanation for the cystic and fibrotic changes associated with long-haul COVID-19 symptoms.

In 2019, a novel single-stranded RNA virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entered the human virosphere in Wuhan, China (Rothan and Byrareddy 2020; Shereen et al. 2020; Hu et al. 2021a). The SARS-CoV-2 virus has been associated with the outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 2019 (COVID-19) (Gorbalenya et al. 2020). The transmissibility and mortality rates of COVID-19 have been alarming. Whereas Middle East respiratory syndrome (MERS) coronavirus took 30 months to infect 1000 people and SARS-CoV took 4 months, SARS-CoV-2 needed just 48 days to infect 1000 people (Boulos and Geraghty 2020). Mortality rates of 38,906 hospitalized patients in the United States, Europe, and China have ranged from 11% to 23% (Dorjee et al. 2020).

CLINICAL OBSERVATIONS

SARS-CoV-2 infection has been associated with a range of illness severity. COVID-19 symptoms can vary from very mild to life-threatening. In an early series of 44,415 people with COVID-19 in China, Wu and colleagues (Wu et al. 2020) noted that 81% of patients had mild disease, 14% had severe disease, and 5% had critical disease. Most patients have presented with fever (94%), cough, and low peripheral oxygen saturation (79%) (Chen et al. 2020; Grasselli et al. 2020; Zhou et al. 2020). Progression of the disease has been characterized by increasing hypoxemia, worsening respiratory function, and eventual multisystem organ failure (Alhazzani et al. 2020).

In addition to acute lung dysfunction, a series of physical characteristics have been linked to the progression of COVID-19 from hospitalization to severe organ dysfunction and eventual death. Comorbidities leading to severe COVID-19 disease include hypertension, diabetes, ischemic heart disease, vascular disease, renal failure, and obesity (www.cdc.gov) (Fig. 1A). These risk factors are strikingly similar to the well-known risk factors for cardiovascular disease. In fact, a community-based prospective cohort study has demonstrated the value of the Framingham risk score for predicting severe disease in COVID-19 (Fig. 1B; D'Agostino et al. 2008; Batty and Hamer 2020). Somewhat unexpectedly for a viral disease, the impact of immunologic risk factors such as autoimmune disease and organ transplantation on COVID-19 severity is less clear (Akalin et al. 2020; Fernández-Ruiz et al. 2020; Fried et al. 2020; Gianfrancesco et al. 2020; Pablos et al. 2020a,b; Pereira et al. 2020; Rodríguez et al. 2020).

Figure 1.

Figure 1.

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Data from a community-based cohort study identified age- and sex-adjusted relative risk (RR) for hospitalizations (A) (Batty and Hamer 2020). The RR for hospitalizations in this cohort correlated closely with the Framingham risk score (quintiles) (R2 = 0.997) (B) (D'Agostino et al. 2008). The error bars reflect 95% confidence intervals.

ANATOMY OF PULMONARY COVID-19

Clues to the pathogenesis of severe COVID-19 disease have been suggested by chest imaging. SARS-CoV-2 is a respiratory virus with relatively high viral loads shedding into the entire aerodigestive tract (He et al. 2020; Noh et al. 2020; Trypsteen et al. 2020). Despite diffuse exposure of the airway epithelium, chest computerized tomography (CT) scanning of COVID-19 lungs characteristically demonstrate patchy ground glass opacities in the peripheral lung (Fig. 2). Distinct from influenza, COVID-19 rarely demonstrates the tree-and-bud pattern of airway bronchorrhea (Shi et al. 2020).

Figure 2.

Figure 2.

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Chest computerized tomography (CT) imaging in patients with documented COVID-19 disease. (A–D) Frontal images demonstrating patchy inflammatory infiltrates in the peripheral lung. (E–F) Transaxial images showing a similar appearance with inflammatory opacities revealing secondary lobules.

The patchy opacities in the peripheral lung corresponds to disease in the anatomic unit of the lung called the secondary lobule. Secondary lobules are polygonal-shaped lung microcompartments supplied by three to five terminal bronchioles (Webb 2006). Bordered by fibrous septa in humans (Bergin et al. 1988), the secondary lobule is notable as the watershed region of the pulmonary and bronchial circulations (Von Hayek 1960; Heitzman et al. 1969; Bergin et al. 1988). COVID-19 typically involves one or more of these structural units. With disease progression, COVID-19 can involve the entire lung.

At the autopsy of patients succumbing to COVID-19, gross examination of the lung characteristically reveals cystic changes and evidence of parenchymal blood clots (Fig. 3A,B). The wet weight of the COVID-19 lungs at autopsy are significantly less than influenza and healthy lungs (Fig. 3C; Ackermann et al. 2020e). The lower wet weight helps explain a surprising clinical presentation: many patients with COVID-19 present with not only hypoxemia and radiographic abnormalities, but also a lack of dyspnea and labored breathing (Dhont et al. 2020). In contrast, most patients with influenza and other life-threatening lung disease commonly have shortness of breath and elevated work of breathing as a result of parenchymal inflammation and pulmonary edema (Loring et al. 2009).

Figure 3.

Figure 3.

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Autopsy anatomy of patients succumbing to COVID-19. (A) Autopsy image of a COVID-19 lung with cystic changes (black arrow) and intravascular clot (white arrow) grossly apparent (scale bar, 1 cm). (B) Microscopic images of H&E-stained lung demonstrated dilated alveolar ducts (scale bar, 200 μm). (C) Wet weight of the lung in autopsy lungs from COVID-19, influenza, and uninfected control lungs (mean ± 1 SD) (Ackermann et al. 2020e). H&E histopathology of the peripheral lung demonstrating vascular blood clots in small vessels (D, white arrow; scale bar, 200 μm) and alveolar capillaries (E, black arrows; scale bar, 50 μm). (F) The relative frequency of thrombi in pulmonary arteries, alveolar capillaries, and veins (mean ± 1 SD) (Ackermann et al. 2020e).

Microscopic evaluation of the autopsy lungs typically demonstrates dilated alveolar ducts likely contributing to the cystic changes observed at autopsy. Air space edema fluid observed histologically in early COVID-19 is responsible for the ground-glass opacities seen on CT scans. The most dramatic microscopic finding, however, has been the presence of intravascular thrombi (Fig. 3D). Whereas COVID-19-associated thrombi have been found in both the pulmonary and systemic circulations (Yin et al. 2021), the dominant finding has been the frequency of microthrombi within alveolar capillaries (Fig. 3E). In our autopsy series, microthrombi in COVID-19 alveolar capillaries were 9 times more frequent than in influenza (H1N1) controls (Fig. 3F; Ackermann et al. 2020e). Although disseminated intravascular coagulopathy has been occasionally observed in COVID-19 (Yin et al. 2021), the concentration of microthrombi in alveolar capillaries indicates a process involving severe local microvascular injury.

MICROVASCULAR INJURY AND INTUSSUSCEPTIVE ANGIOGENESIS

The striking prevalence of alveolar capillary thrombi in COVID-19 suggests a vascular injury directly linked to the SARS-CoV-2 virus. To evaluate the pulmonary capillary network in patients dying of COVID-19, we performed corrosion casting of the autopsy lungs. Corrosion casting is an investigative method that perfuses the vascular system with a low viscosity resin. The resin polymerizes within the microcirculation. To visualize the intraluminal polymer, the tissue surrounding the cast is digested and removed. The remaining cast of the lumen is subsequently examined for anatomic details by scanning electron microscopy (SEM) (Konerding 1991; Lametschwandtner and Aharinejad 1997). SEM is well-suited to this analysis since it is a high-resolution imaging technique that is sufficiently scalable to characterize the topography of vascular networks as well as the morphology of individual vessels.

Because corrosion casting and SEM can evaluate the entire microcirculation, a particularly valuable feature is the ability to distinguish the pulmonary from bronchial circulation. The dual circulations of the lung are often conflated in discussions of the lung microcirculation, but they have distinctive roles in not only normal lung function, but also pulmonary infections. In normal lungs, the bronchial circulation delivers oxygenated blood at systemic blood pressure; however, the bronchial circulation is a relatively low flow system. The normal bronchial circulation delivers <3% of the cardiac output (Deffebach et al. 1987). In the presence of tissue ischemia or parenchymal infection, the bronchial circulation can immediately increase systemic blood flow (Deffebach et al. 1987).

Corrosion casting and SEM of the bronchial circulation have demonstrated anatomic features responsible for the regulation of recruitable bronchial blood flow. Sperrarterien is the German word for blocked arteries. First described by von Hayek (1960), and retained by Krahl (Krahl 1964), Sperr arteries are muscular arteries that appear capable of complete vasoconstriction and the blockage of blood flow (Schraufnagel et al. 1995). Bronchial arteries also provide vaso vasorum for pulmonary blood vessels as well as connections with capillary networks within secondary lobules. The intercommunication of the bronchial and pulmonary capillaries in the peripheral lung is likely an important mechanism for avoiding tissue ischemia. In the setting of acute ischemia, massive bronchial arterial arteriogenesis and angiogenesis have been described (Karsner and Ghoreyeb 1913; Jandik et al. 1993; Mitzner and Wagner 2004). In both ischemia and infections, the bronchial circulation facilitates the delivery of oxygenated blood and inflammatory cells while avoiding the mismatching of ventilation and perfusion that would accompany an increase in local pulmonary blood flow (Ravnic et al. 2007).

In COVID-19 autopsy specimens, corrosion casts of the microcirculation have consistently demonstrated markedly abnormal vessels in the gas exchange beds of the secondary lobules. The most notable findings have been luminal surface irregularities consistent with endothelial inflammation and destruction (Fig. 4A,B). In most autopsy specimens, bronchial vessels feeding the secondary lobules are dilated and tortuous suggesting bronchial artery hypertrophy and vascular remodeling.

Figure 4.

Figure 4.

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Endothelialitis and endothelial injury. Corrosion casts of control (A) and COVID-19 (B) lungs (scale bars, 100 μm) examined by scanning electron microscopy (SEM). (C) SEM of intussusceptive pillars in COVID-19 (scale bar, 10 μm). (D) Transmission electron microscopy demonstrating virus-like particles in the endothelial cells (yellow ellipse; scale bar, 10 μm). (E) Immunohistochemistry with antispike protein monoclonal antibody staining of COVID-19 endothelial cells (arrow). (F) SARS-CoV-2 probes demonstrating the presence of viral nucleic acids by fluorescent in situ hybridization (FISH) (arrows) (Ackermann et al. 2020b).

Beyond endothelial irregularities and increased bronchial perfusion, corrosion casting and SEM analysis of COVID-19 autopsy lungs has demonstrated significant amounts of intussusceptive (nonsprouting) angiogenesis. The process of nonsprouting or “intussusceptive” angiogenesis was initially characterized in 1986 (Caduff et al. 1986). The distinctive feature of intussusceptive angiogenesis is the intussusceptive pillar—a cylindrical microstructure that spans the lumen of small vessels and capillaries. The extension of the pillar down the axis of the blood vessel appears to be a mechanism for creating two lumens from a single vessel (Lee et al. 2011). This process of vascular duplication has been frequently cited as a mechanism for microvascular network expansion with a minimal requirement for endothelial cell proliferation (Mentzer and Konerding 2014). Consistent with an ongoing process of intussusceptive angiogenesis, numerous pillars and split vessels have been observed in COVID-19 secondary lobules. Supporting the notion of intussusceptive angiogenesis as an adaptive response to severe disease, the longer the patient's hospitalization, the greater the prevalence of these markers of intussusceptive angiogenesis (Ackermann et al. 2020e).

Using finite element flow models, we have shown that pillars form in microhemodynamic “dead zones” within the vessel (Filipovic et al. 2009; Lee et al. 2011); that is, pillars form in flow regions with shear stress below 1 dyn/cm2 (Lee et al. 2011). Because areas of low shear stress are not always associated with intussusceptive pillars, we have postulated a permissive role for low shear stress in pillar development. Regions of low wall shear stress are necessary, but not sufficient for the development of intraluminal pillars. In addition to low shear stress, endothelial cell activation from extravascular and/or intraluminal signals appear to be required for pillar formation and network expansion (Lee et al. 2011). In the context of COVID-19, potential candidates for endothelial activation include viral infection, perivascular inflammation, and tissue ischemia.

ENDOTHELIAL INJURY AND ENDOTHELIALITIS

To investigate the markedly abnormal microvascular endothelium in COVID-19, we performed serial transmission electron microscopy (TEM) of the affected secondary lobules. TEM demonstrated endothelial cells with dramatic ultrastructural changes consistent with cell death, namely, cell swelling, dissolution of intercellular junctions, and detachment from the basement membrane (Ackermann et al. 2020e). The consistency of these findings has suggested that microvascular injury in secondary lobules of the lung is an important feature of COVID-19 pathophysiology.

The cause of the endothelial injury is less clear. Although the morphology of the lung endothelial ultrastructure is significantly compromised by autopsy-related autolysis and aldehyde fixation, viral particles have been consistently identified within COVID-19 endothelial cells (Fig. 4D). The virus-like particles have been demonstrated at various stages of capsid maturation. Immunohistochemistry has confirmed the presence of spike proteins within endothelial cells (Fig. 4E). In addition, fluorescence in situ hybridization has confirmed the presence of viral nucleic acid within endothelial cells (Fig. 4F). Although functional replication of SARS-CoV-2 in endothelial cells is difficult to unequivocally establish, our results are consistent with the direct viral infection of endothelial cells in COVID-19.

Endothelial injury caused by the SARS-CoV-2 virus provides a useful explanation for two puzzling clinical observations in COVID-19. First, a subset of patients with COVID-19 lack breathlessness or dyspnea in the setting of severe hypoxemia. Guan reported dyspnea in only 18.7% of 1099 hospitalized COVID-19 patients despite clinically significant hypoxemia (Guan et al. 2020). The absence of symptoms—sometimes referred to as “happy” or “silent” hypoxia—is notable since most patients with other forms of lung dysfunction sense ineffective ventilation and increased work of breathing (Couzin-Frankel 2020; Dhont et al. 2020). As noted earlier, the lack of pulmonary edema and the preserved mechanics of lung ventilation is consistent with the relatively low wet weight of COVID-19 lungs at autopsy (Ackermann et al. 2020e).

Second, a subset of intensive care patients demonstrates marked improvement in oxygenation by changing from a supine to prone position—a positional change commonly referred to as “proning.” In the setting of severe COVID-19, a supine patient unresponsive to 100% inspired oxygen may dramatically improve oxygenation with a change to a prone position (Pugliese et al. 2018; Moran and Graham 2021). Although this positional effect can be seen in other respiratory distress syndromes (Scholten et al. 2017), the magnitude and consistency of the response in COVID-19 patients has been particularly notable.

An explanation for these observations is the disruptive effects of COVID-19 on vascular wall integrity and information transfer within the lung. Both happy hypoxia and positional effects reflect functional shunting; that is, the failure of the pulmonary circulation to appropriately distribute blood flow. In normal circumstances, blood flow to inefficient or hypoxic regions of the lung is restricted by vasoconstriction (Sylvester et al. 2012). Hypoxic vasoconstriction requires the upstream transfer of information mediated by endothelial cells (Wang et al. 2012; Secomb et al. 2013). In the case of COVID-19, endothelial injury results in a disruption of these conducted responses. The result is a mismatch of lung perfusion and alveolar oxygen that appears to be out of proportion to the global lung injury. We speculate that other organs similarly dependent upon perfusion matching, such as the brain, may also be adversely affected by endothelial injury.

PERIVASCULAR IMMUNE RESPONSE

In most systemic illnesses, there are only small variations in peripheral blood lymphocyte counts (Blum and Pabst 2007). A distinctive feature of COVID-19—and a feature shared by severe influenza (Lalueza et al. 2019)—is the selective decline in peripheral blood lymphocyte counts. The decrease in lymphocyte counts has generally correlated with the severity of the disease; patients who die of COVID-19 have a lower blood lymphocyte count than survivors (Ruan et al. 2020). A general trend is that CD8+ T cells are a lower percentage of the peripheral blood than CD4+ T cells (Li et al. 2004). As a result, the neutrophil-to-CD8+ T-cell ratio has been a particularly powerful prognostic indicator (Liu et al. 2020).

A potential reason for COVID-19-induced lymphopenia is the direct cytopathic effect of the virus. Both MERS-CoV and SARS-CoV directly infect human T cells and induce apoptotic cell death (Gu et al. 2005; Chu et al. 2016). We have examined COVID-19 and influenza autopsy lungs for the expression of the putative SARS-CoV-2 receptor ACE-2. In both COVID-19 and influenza, ACE-2 expression was elevated in endothelial cells, alveolar cells, and lymphocytes (Ackermann et al. 2020e). The inducible expression of ACE-2, and the presence of ACE-2 independent pathways (Wang et al. 2020), leaves unanswered the possibility of SARS-CoV-2-induced destruction of recirculating lymphocytes.

Another potential explanation for COVID-19 lymphopenia is the sequestration of recirculating lymphocytes in target organs (Fauci and Dale 1975). In normal circumstances, lymphocytes recirculate throughout the blood and lymphatic system (Gowans and Knight 1964)—presumably as a mechanism to distribute systemic immunity. These recirculation patterns, however, are altered by antigen exposure and lymphocyte activation states (Hamann et al. 2000; Weninger et al. 2001). In COVID-19, the likely sites of lymphocyte activation and sequestration include the lungs, gastrointestinal tract, bone marrow, regional lymph nodes, and spleen (Gobin et al. 1992). Support for sequestration being the mechanism of lymphopenia, rather than direct cytopathic effects of the virus, is the rapid increase in circulating lymphocyte counts observed in patients recovering from COVID-19 (Liu et al. 2020).

To explore the evidence for lymphocyte sequestration in the lung, we performed OPAL 7-plex immunohistochemistry of the lungs of COVID-19 and influenza autopsy specimens. Most of the lymphocytes were in the perivascular compartment (Fig. 5). The angiocentric recruitment of lymphocytes was reminiscent of allogeneic immune response observed during lung transplant rejection or graft-versus-host disease (Rawn et al. 2000). The selective angiocentric recruitment was distinct from the diffuse lymphocyte infiltration observed in interstitial lung diseases (ILDs) (Ackermann et al. 2020d). We found fewer than expected lymphocytes in the interstitial compartment and almost no T cells in the alveolar compartment.

Figure 5.

Figure 5.

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Pulmonary immune response. (A–C) Immunohistochemistry of the perivascular mononuclear infiltration in the perivascular, interstitial, and alveolar compartments of the COVID-19 lung. Cells were characterized as T-cell (CD3) subsets (CD4, CD8), myeloid cells (CD15, CD68), and B cells (CD20). (D) Multiplex fluorescence immunohistochemistry identified the inflammatory infiltrate to consist predominantly of T cells: CD3 (white), CD4 (green), CD8 (yellow), CD20 (purple), CD68 (red), and DAPI nuclear stain (blue). Clot is noted in the vessel lumen (arrow; scale bar, 100 µm). (E) A CD4+ lymphocyte migrates into interstitial lung lymphatics (arrow; scale bar, 10 µm).

An interesting observation has been the contrasting proportions of CD4+ and CD8+ lymphocytes in COVID-19 and influenza lungs. Consistent with observations in the peripheral blood, we found a dominant population of CD4+ T cells in COVID-19. In contrast, the CD8+ T cells were the dominant population in influenza autopsy lungs (Fig. 5A). The current explanations for this subset inversion include differences in target antigens as well as lymphocyte exhaustion. Immunologically dominant COVID-19 antigens may be restricted by MHC class II molecules leading to clonal expansion of CD4+ cytolytic T lymphocytes in the lung (Kaneko et al. 2021). Alternatively, CD4+ cells may be dominant in COVID-19 because of a relative decline in the prevalence of CD8+ cells due to lymphocyte exhaustion. A phenomenon observed in chronic viral infection, exhaustion is the gradual loss of function and eventual physical depletion of the CD8+ cells (Zheng et al. 2020; Kusnadi et al. 2021).

In the clinical course of COVID-19, the angiocentric recruitment of lymphocytes into the lung is influenced by the innate immune system. Critical for recognizing and controlling infections through the release of cytokines and chemokines, the host innate immune system can recognize pathogen-associated molecular patterns (PAMPs) via pattern-recognition receptors (PRRs) during infections. Of the five PRR families (Amarante-Mendes et al. 2018), early work suggests that Toll-like receptors (TLRs), including cell membrane–bound TLR-2/7 (Zheng et al. 2021), are particularly active in producing inflammatory cytokines in response to the SARS-CoV-2 virus. TLR expressed on myeloid, stromal, and endothelial cells in the lung may play a pivotal role in the clinical syndrome referred to as “cytokine storm” (Hu et al. 2021b; Karki et al. 2021).

Observations from COVID-19 suggest that the primary function of the humoral immune system is the prevention of viremia and the associated vascular phase of the disease. The evidence for this function is that both the vaccines and monoclonal antibody cocktails are very effective at preventing severe disease. Despite this prophylactic benefit, vaccines, monoclonal antibodies, and convalescent serum have little value in established disease (Li et al. 2020; Marovich et al. 2020). The limited therapeutic value is not because of a failure to produce antibodies. Patients with severe disease have higher titers and higher affinity antibodies than mild disease (Li et al. 2020). These observations suggest, at minimum, that antibodies specific for viral particles and viral proteins have a large impact on preventing, and a limited impact on treating, the vascular phase of COVID-19 (Hansen et al. 2020; Yuan et al. 2020). The explanation for these therapeutic limitations and the complementary role played by the cellular immune system remain open questions.

MICROANATOMY AND MOLECULAR PROFILING

Despite similarities in the respiratory phases of influenza and COVID-19, a distinguishing feature of COVID-19 is the angiocentric or vascular phase of the disease. As demonstrated in gross and microscopic studies of autopsy lungs, COVID-19 is associated with distortion of microvascular networks, disruption of endothelial vasoregulation, and occlusion of gas exchange capillaries in the lung. The consequence is not only ineffective gas exchange, but also tissue ischemia. Morphologic evidence indicating severe tissue ischemia is the dramatic increase in intussusceptive angiogenesis observed within COVID-19 lungs (Ackermann et al. 2020e). Innumerable intraluminal pillars and split blood vessels—both signatures of intussusceptive angiogenesis—were spatially correlated with ischemic secondary lobules (Ackermann et al. 2020c,e). Also consistent with a response to tissue ischemia, the degree of intussusceptive angiogenesis appears to increase with the severity of disease and the length of hospitalization (Ackermann et al. 2020a,e).

Localized tissue ischemia within the lung is normally compensated by the bronchial circulation (Baile 1996). The bronchial vessels branch off the descending aorta to perfuse the proximal airways as well as the fibrous septa of secondary lobules in the lung (Baile 1996). The importance of the bronchial circulation in preventing local tissue ischemia is underscored by observations in lung transplantation and airway reconstructive surgery—clinical scenarios in which the bronchial circulation is disrupted. In these cases, pulmonary thromboembolism can result in fatal tissue infarction (Kroshus et al. 1995).

An illustration of microischemia within a secondary lobular microcompartment is provided by high-resolution synchrotron imaging (Fig. 6A; Walsh et al. 2021). Core biopsies of COVID-19 lungs have demonstrated end-stage fibrotic changes in some secondary lobules (Fig. 6B, yellow). Intriguingly, neighboring secondary lobules can demonstrate remarkably preserved lung microstructure. Based on semiquantitative estimates of blood-filled vessels, hypovascular fibrotic secondary lobules are frequently juxtaposed to hypervascular secondary lobules (Fig. 6C, inset). The striking contrast of fibrotic remodeling and preserved lung structure suggests a critical conclusion. The patchy distribution of COVID-19 in the lung is a result of local microischemia. In the fibrotic secondary lobules, the bronchial circulation and intussusceptive angiogenesis are unable to overcome the ischemic vasculopathy. The secondary lobules with insufficient perfusion and persistent microischemia suffer progressive fibrotic remodeling.

Figure 6.

Figure 6.

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Summary of NanoString transcriptional profiles of patients with COVID-19 and influenza. (A) Randomly colored projection of secondary lobular anatomy superimposed on a whole-lung synchrotron section. (B) Synchrotron images of a core lung biopsy of a COVID-19 autopsy lung. The portion of the biopsy demonstrating fibrotic remodeling (a) is colored yellow for presentation purposes (image courtesy of Dr. Claire Walsh and colleagues at the Centre for Advanced Biomedical Imaging, University College, London, UK). Scale bar, 2 mm. The secondary lobule with preserved anatomy is juxtaposed (b). (C) Higher resolution image shows the electron-dense, blood-filled vessel at significantly higher density than in the remodeled region (inset). (D) A NanoString Venn diagram reflecting the amount of shared gene expression between COVID-19 autopsy lungs and autopsy lungs obtained from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and alveolar fibroelastosis (AFE). (E) The NanoString profiles comparing patients with COVID-19 and influenza (column 1 and 2). Also shown are the profiles of COVID-19 changes over their hospital course (column 3) and the transcriptional profiles of COVID-19 samples taken from patients with high levels of intussusceptive angiogenesis (IA). The transcriptional profiles are summarized by the false discovery rate (FDR) and normalized pathway enrichment score (NES). (F) Schematic summary of the bronchial circulation demonstrating the intercommunication with the pulmonary circulation at the level of the secondary lobule.

The COVID-19-associated fibrotic remodeling is distinct from the fibrosis associated with ILD. Usual interstitial pneumonia (UIP), the commonest variant of the fibrosing ILD, is associated with heterogeneous and patchy fibrosis. Most of the fibrosis is subpleural and predominantly associated with the basilar regions of the lung. Although UIP is associated with angiogenesis, it typically demonstrates more sprouting than intussusceptive angiogenesis (Ackermann et al. 2020d). Moreover, the angiogenesis is associated with a chaotic tumor-like aberrant distribution of vessels. Other common ILD injury patterns, including nonspecific interstitial pneumonia (NSIP) and alveolar fibroelastosis (AFE), are associated with enhanced intussusceptive angiogenesis; however, both NSIP and AFE demonstrate a diffuse and more uniform pattern of inflammation than most patients with COVID-19. To explore the unique features of COVID-19 fibrotic remodeling, we compared NanoString molecular profiling of COVID-19, UIP, NSIP, and AFE. Although there was some transcriptional overlap, gene expression in COVID-19 was distinct from the common forms of ILD (Fig. 6D).

COVID-associated fibrotic remodeling is also distinct from the molecular profiles of influenza lungs (Fig. 6E). Similar to COVID-19 histopathology, influenza pneumonia is associated with small vessel and capillary thromboses as well as interstitial edema and inflammatory infiltrates (Taubenberger and Morens 2008); however, influenza is typically airway-centric with widespread necrotizing bronchiolitis and diffuse alveolar damage. The molecular profile of autopsy specimens from influenza patients is consistent with an airway-centric antiviral response. Host pathways in response to influenza are notable for type I interferon signaling and viral defense pathways. In contrast, COVID-19 lungs demonstrate diminished expression of viral defense pathways, but also a striking increase in pathways linked to angiogenesis, collagen formation, and extracellular matrix organization. Molecular profiling of COVID-19 lungs consistently demonstrate enhanced expression of intussusceptive angiogenesis-related genes, such as VEGFA, TIE2, and HIF1A (Ackermann et al. 2020e). These findings highlight the unique molecular signature of the vascular phase of COVID-19.

Finally, we performed a small pilot study of lungs from patients who had survived moderate to severe COVID-19—in most cases, lung tissue was resected as treatment for lung cancer. These patients had recovered from symptomatic COVID-19 from 1 to 3 months prior to undergoing surgical lobectomy. Approximately 40% of these patients had histologic evidence of patchy fibrotic remodeling. Patients with fibrotic remodeling typically had a complicated recovery after surgery including postoperative dyspnea, fatigue, and the prolonged need for supplemental oxygen—symptoms consistent with long-haul COVID-19. In the remainder of the patients, an encouraging finding was the absence of any histopathologic evidence of COVID-19. Even in areas of prior COVID-19-associated radiographic opacities, the lung parenchyma appeared both grossly and microscopically normal. In this latter group of patients, we speculate that the vascular phase of COVID-19 associated with localized tissue ischemia was adequately addressed by the induction of both enhanced bronchial blood flow and intussusceptive angiogenesis. An important focus of future work will be identifying the determinants of this crucial turning point in COVID-19.

SUMMARY

The pathophysiology of COVID-19 has been puzzling because it represents respiratory viral transmission in all patients, complicated by a life-threatening vascular phase in a subset of patients. The vascular phase of COVID-19 involves the destruction of endothelial cells as well as intraluminal thrombosis. Endothelial cell destruction compromises the conducted responses that regulate ventilation-perfusion matching in the lung. The result is systemic hypoxemia that aggravates the underlying tissue ischemia. The discrete spatial distribution of COVID-19 is a reflection of the secondary lobule—the lung anatomic compartment that is the watershed of the pulmonary and bronchial circulation (Fig. 6F). We speculate that in many patients, the bronchial circulation is adequate to avoid tissue ischemia; however, severe COVID-19 is linked to compromised or insufficient bronchial circulation. In most patients with COVID-19, intussusceptive angiogenesis represents an adaptive response to mitigate tissue ischemia. Irreversible tissue ischemia leads to the cystic and fibrotic changes that are associated with long-haul COVID-19 symptoms. The implications of these observations for patient care include the importance of supplemental oxygen and judicious anticoagulation, that is, therapies intended to limit tissue ischemia and avoid subsequent fibrotic remodeling.

Footnotes

Editors: Diane R. Bielenberg and Patricia A. D'Amore

Additional Perspectives on Angiogenesis: Biology and Pathology available at www.cshperspectives.org

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