An Integrated Radiologic-Pathologic Understanding of COVID-19 Pneumonia

Abstract

This article reviews the radiologic and pathologic findings of the epithelial and endothelial injuries in COVID-19 pneumonia to help radiologists understand the fundamental nature of the disease. The radiologic and pathologic manifestations of COVID-19 pneumonia result from epithelial and endothelial injuries based on viral toxicity and immunopathologic effects. The pathologic features of mild and reversible COVID-19 pneumonia involve nonspecific pneumonia or an organizing pneumonia pattern, while the pathologic features of potentially fatal and irreversible COVID-19 pneumonia are characterized by diffuse alveolar damage followed by fibrosis or acute fibrinous organizing pneumonia. These pathologic responses of epithelial injuries observed in COVID-19 pneumonia are not specific to SARS-CoV-2 but rather constitute universal responses to viral pneumonia. Endothelial injury in COVID-19 pneumonia is a prominent feature compared with other types of viral pneumonia and encompasses various vascular abnormalities at different levels, including pulmonary thromboembolism, vascular engorgement, peripheral vascular reduction, a vascular tree-in-bud pattern, and lung perfusion abnormality. Chest CT with different imaging techniques (eg, CT quantification, dual-energy CT perfusion) can fully capture the various manifestations of epithelial and endothelial injuries. CT can thus aid in establishing prognosis and identifying patients at risk for deterioration.

© RSNA, 2023

Summary

Understanding integrated radiologic and pathologic findings of epithelial and endothelial injuries in COVID-19 pneumonia can facilitate timely and appropriate patient management strategies.

Essentials

• ■ Lung epithelial injury in COVID-19 results from the direct toxicity of SARS-CoV-2 and the immune response; the disease course can be separated into two categories, which partly overlap: mild resolving and severe progressing COVID-19.

• ■ Histopathologic findings in mild resolving COVID-19 pneumonia show nonspecific pneumonia or the organizing pneumonia pattern; at CT, these correspond to peripheral or peribronchovascular distribution of ground-glass opacities (GGOs) and small areas of consolidations representing organizing pneumonia.

• ■ In patients with severe progressing COVID-19, acute fibrinous organizing pneumonia and diffuse alveolar damage are major histopathologic features; on radiologic images, these correspond to GGO (in exudative-phase diffuse alveolar damage) and consolidations (in proliferative- to fibrotic-phase diffuse alveolar damage or acute fibrinous organizing pneumonia).

• ■ Endothelial injury is a key factor for the pathogenesis of acute respiratory distress syndrome in COVID-19, resulting in pulmonary thromboembolism, vascular engorgement, reduced peripheral vascularity, the vascular tree-in-bud pattern, and perfusion abnormality.

Introduction

The COVID-19 pandemic has spread worldwide, resulting in at least 639 million confirmed cases and 6.6 million global deaths as of December 1, 2022 (1). Since the prompt development and administration of COVID-19 vaccines, 71% of the world population has received at least one vaccine dose (2). However, even for fully vaccinated individuals, vaccine breakthrough infections—defined as infections with SARS-CoV-2 at least 14 days after completion of the primary vaccination series—can occur because full vaccination is not 100% effective for preventing illness (3). Nevertheless, even if breakthrough infections occur, fully vaccinated individuals have less severe disease courses and complications (4–7). As a result of genetic variations of SARS-CoV-2 during viral replication (8,9), several variants of SARS-CoV-2 have been reported worldwide throughout the pandemic with increased transmissibility and evasiveness of treatments and vaccines (eg, the Delta and Omicron variants). Fortunately, the Omicron variant, the latest variant of concern, predominantly involves the proximal airway and is less virulent, resulting in lower rates of hospitalization, intensive care unit admission, and mortality (10–12).

Chest imaging plays a vital role in narrowing down the differential diagnosis, detecting complications, and potentially prognosticating patients with COVID-19 (13,14). Since the early stage of the pandemic, radiologists have promptly responded to COVID-19 by identifying the CT findings of COVID-19, which include ground-glass opacities (GGOs) with or without consolidation, GGOs with intralobular lines (ie, a crazy paving appearance), and the reverse halo sign or other findings of organizing pneumonia in peripheral and bilateral distributions. Those typical findings were incorporated into standardized reporting systems, such as the RSNA classification and the COVID-19 Reporting and Data System, or CO-RADS (15–23). Typical CT findings of COVID-19 can overlap with CT findings of differential diagnoses (ie, cryptogenic organizing pneumonia or influenza pneumonia), and guidelines have recommended against the first-line diagnostic use of CT scans for COVID-19 (16). Nevertheless, chest CT helped handle cases that were diagnostically challenging based solely on a polymerase chain reaction test (24). Chest imaging also helps detect COVID-19–associated complications, such as pulmonary thromboembolism, superimposed pneumonia other than COVID-19, and heart failure, particularly when patients with COVID-19 have suddenly worsening clinical symptoms or signs (13,14,25). Furthermore, chest radiographic and CT assessments of pneumonia extent and characteristics can be used for the prognosis of patients with COVID-19 (26–28).

The purpose of this article is to review the relationship between pathologic findings of epithelial and endothelial injuries in COVID-19 pneumonia and the corresponding radiologic findings of SARS-CoV-2 infection.

Two Different Disease Courses of COVID-19 Pneumonia Depending on Viral Injury and Immune Response

Although patients with COVID-19 have heterogeneous clinical courses, and the mechanisms of this heterogeneity are not fully understood, they are mainly separable into two distinct courses (29–32). Approximately 70%–80% of patients with COVID-19 have mild symptoms with favorable outcomes and predominantly GGOs at chest imaging (29–32). The other 20%–30% of patients have moderate to severe COVID-19 and are at risk for progressing to acute respiratory distress syndrome (ARDS). These patients can have symptoms and signs of respiratory difficulty and extensive GGOs and consolidations at chest imaging (29–35). Although we have dichotomized COVID-19 pneumonia into these two disease courses, there can be considerable overlap between them, and COVID-19 pneumonia initially manifesting as a mild disease can progress to a severe disease course. The risk factors for developing unfavorable outcomes, such as ARDS and mortality, include older age, male sex, current smoking, a high body mass index (>25 kg/m²), comorbidities such as hypertension and diabetes mellitus, symptoms or signs of respiratory distress, superimposed bacterial infection, the presence of radiologic abnormalities, and abnormal laboratory test results (eg, a decreased white blood cell count and elevated levels of lactate dehydrogenase, direct bilirubin, C-reactive protein, and d-dimer) (31,33,34,36,37).

Although direct cytotoxicity of SARS-CoV-2 initiates lung parenchymal injuries, virus-triggered immune reactions are also responsible for these two different disease courses (38–40). In other words, despite the identification of SARS-CoV-2 in injured lung tissues, viral injury itself cannot explain the temporal and spatial disconnect between the presence of the virus (as shown by viral RNA or protein) and pulmonary damage, as well as the evidence of mortality benefits of anti-inflammation therapy (eg, corticosteroids and interleukin 6 blockade) (41–43). Indeed, several autopsy studies have reported little viral proliferation or replication and simultaneous active dysregulated inflammatory responses in deceased patients with severe COVID-19, indicating the continuous progression of immune responses and lung injury during severe COVID-19 despite controlling the virus (44–47).

To summarize, different clinical manifestations in individuals infected with SARS-CoV-2 are caused not only by the direct toxicity of the virus but, more importantly, by virus-triggered immunopathologic effects.

Pathophysiologic Features of the Lung Parenchymal Response to Acute Lung Injury

The pathophysiologic lung parenchymal response to acute injuries is similar across a wide range of injury causes, including SARS-CoV-2 (48). Organization is a common general response to injury in the lung, pathologically characterized by fibroblast proliferation evoked from damage to the alveolar-vascular barrier in the alveolar wall (48). The basement membrane, the formal term for the alveolar-vascular barrier, is a thin layer of specialized extracellular matrix fused with alveolar epithelial and capillary endothelial cells (49). It serves the functions of a barrier, compartmentalization, selective filtration, and a reservoir for various growth factors and cytokines (49). Lung organization is initiated by the leakage of protein-rich exudate through the basement membrane into the alveolar space, followed by fibroblast migration from the interstitium, fibroblast differentiation into myofibroblasts, and the formation of organizing fibroblastic tissue and fibrous tissue (48) (Fig 1, Table).

Figure 1:

A schematic diagram of the histopathologic findings of COVID-19 pneumonia. The histopathologic features of COVID-19 pneumonia span a diverse spectrum encompassing epithelial, endothelial, and airway injuries. For epithelial injury, patients with mild and reversible damage histopathologically show nonspecific pneumonia and the organizing pneumonia pattern, which is in line with the radiologic organizing pneumonia pattern of a peripheral or peribronchovascular distribution of ground-glass opacities (GGOs) and small areas of consolidations. In patients with potentially fatal and irreversible disease, acute fibrinous organizing pneumonia and diffuse alveolar damage are the major histopathologic features, radiologically represented as GGO (in exudative-phase diffuse alveolar damage) and consolidations (in proliferative- to fibrotic-phase diffuse alveolar damage or acute fibrinous organizing pneumonia). Endothelial injuries in COVID-19 include pulmonary thromboembolism, vascular engorgement, reduced peripheral vascularity, the vascular tree-in-bud pattern, and perfusion abnormality. Bronchiolitis obliterans as an airway injury is also reported.

Key Clinical, Radiologic, and Pathologic Features of Epithelial, Endothelial, and Airway Injuries in COVID-19

The integrity of the alveolar-vascular basement membrane is critical to determine whether the injured lung parenchyma has been remodeled into normal architecture or replaced with fibrous tissue (48,50–52) (Fig 2). If the basement membrane is intact, injured lung tissues undergo re-epithelialization and re-endothelialization while removing fibroblasts, eventually returning to normal lung architecture (48,50). On the contrary, if the basement membrane is disrupted, collapsed alveoli elicit persistent fibroblast activation (50). This phenomenon reinforces the formation of organizing fibroblastic tissue with accumulating extracellular matrices, leading to the establishment of fibrosis (50). These sequential pathologic lung parenchymal responses are represented by acute lung injury and can show a histologic spectrum of diffuse alveolar damage, acute fibrinous and organizing pneumonia, and organizing pneumonia according to the temporal difference between acute to subacute injury and the degree of acute lung injury (48,51,53).

Figure 2:

A diagram for lung parenchymal response to acute lung injury in COVID-19. (A) When SARS-CoV-2 is transmitted to the host, it infects type II alveolar epithelial cells in the lung parenchyma, followed by monocyte recruitment, cytokine release, pneumocyte apoptosis, and macrophage recruitment. (B) If the alveolar-vascular basement membrane is intact, injured lung tissues undergo re-epithelialization and re-endothelialization while removing fibroblasts, eventually returning to the normal lung architecture. (C) In contrast, if the basement membrane is disrupted, persistent fibroblast activation continues to the formation of organizing fibroblastic tissue with accumulating extracellular matrices, leading to the establishment of fibrosis.

Conventionally, diffuse alveolar damage is the most severe radiologic and histopathologic type of acute lung injury associated with ARDS (51,52). It results from alveolar-vascular basement membrane injury and disruption, causing fluid and exudate transmigration (51,52). Diffuse alveolar damage consists of three histopathologic phases: the acute phase (exudative phase; within 1 week), with intra-alveolar hyaline membrane formation and edema, as well as alveolar wall thickening, which radiologically manifests as diffuse GGO and consolidation with an anteroposterior density gradient (48); the subacute phase (proliferative phase; 1 week after), characterized by microscopic organization of fibrin followed by fibroblast migration, the proliferation and secretion of loose collagen, and the incorporation of hyaline membranes into organizing fibrotic tissue in airspaces, alveolar ducts, and alveolar walls; and the chronic phase (fibrotic phase; weeks to months after), with progressive architectural remodeling by interstitial fibrosis (51,52,54). Dependent predominant GGO and consolidation representing lung organization and alveolar collapse and fibrosis changes, including reticulation and traction bronchiectasis, evolve in the subacute and chronic phases (48). Acute fibrinous organizing pneumonia is a distinct histopathologic pattern of acute lung injury in the spectrum from diffuse alveolar damage to organizing pneumonia (51,52,54). Reflecting this, acute fibrinous organizing pneumonia has a radiologic spectrum in line with its corresponding clinical course: Diffuse alveolar damage pattern in an acute fulminant clinical course and organizing pneumonia pattern in a subacute indolent course (48,55). It is characterized by intra-alveolar fibrin deposition forming patches of fibrin balls and organizing pneumonia from fibroblast migration and collagen secretion by fibrin aggregates, without classic hyaline membranes and eosinophilia (51,52,54). However, a great deal of overlap exists between acute fibrinous organizing pneumonia and diffuse alveolar damage or organizing pneumonia in terms of clinical courses and radiologic and pathologic findings (48). Organizing pneumonia has intraluminal tufts of plump fibroblasts and collagen tissue in alveolar ducts and distal airspaces (51,52,54). Organizing pneumonia predominantly manifests as peripheral or peribronchovascular GGO and consolidation, with reversed halo or perilobular opacities that often migrate from one parenchyma to another (48).

Radiology-Pathology Correlation in Mild Resolving COVID-19

When SARS-CoV-2 is transmitted to the host, the virus preferentially infects type II alveolar epithelial cells via the angiotensin-converting enzyme II receptor, which is known to be the main entrance of the virus (56,57). Afterward, monocytes release cytokines that induce apoptosis in pneumocytes and recruit macrophages (56,57). The recruited macrophages increase capillary permeability, followed by neutrophil recruitment and aggregation in the interstitium and alveolar space (56,57). Through a series of these inflammatory cascades, various proteins in the blood transmigrate to the interstitium and alveolar space, causing interstitial and alveolar edema (56).

In most cases, patients with mild COVID-19 have a reversible disease course without progression into ARDS (29–32). Thus, the inflammatory process described earlier does not continue and break the alveolar-vascular basement membrane (48,50,56). Instead, the histopathologic findings in early-phase COVID-19 pneumonia typically represent nonspecific pneumonia or the organizing pneumonia pattern (Fig 3): type II pneumocyte hyperplasia, interstitial inflammation, intra-alveolar edema with proteinaceous exudates, and ultimate organization, but without fibrin or hyaline membranes and only scanty fibrosis (57–59). The deposition of leaked inflammatory cells and fibrin can form intra-alveolar organizing fibroblastic tissues transiently but are eventually resolved and remodeled by epithelial cell proliferation (48,50,60).

Figure 3:

A representative example of incidental histopathologic findings of early and mild COVID-19 in a 53-year-old man. The patient underwent right upper lobectomy with mediastinal lymph node dissection for lung adenocarcinoma. A week after surgery, the patient reported high fever and sore throat and was confirmed to have COVID-19 at real-time reverse-transcription polymerase chain reaction testing. A specimen from the extracted right upper lobe and stainted with hematoxylin and eosin shows potential early COVID-19 histopathologic findings: focal expansion of alveolar walls with inflammatory cell infiltration (black arrows), type II pneumocyte hyperplasia (white arrows), and some alveolar macrophages in the airspaces (arrowheads) (scale bar: 100 μm). The patient improved and was discharged without clinical or radiologic deterioration.

In line with these histopathologic findings, a CT pattern consistent with organizing pneumonia is a predominant feature in patients with mild COVID-19 (58,61,62) (Fig 4). Indeed, a peripheral or peribronchovascular distribution of GGOs and small areas of consolidations representing organizing pneumonia patterns at CT have been frequently reported in up to 50%–70% of patients with mild COVID-19 (14,16,48,58,60–66). Of course, lung parenchymal fibrosis may manifest as one of the CT findings in organizing pneumonia, such as perilobular thickening, traction bronchiectasis, or focal volume loss (48,58). Other reported CT features in patients with mild COVID-19 include GGO with interstitial thickening (ie, a crazy paving appearance), perilobular opacities, and the reversed halo sign (58,66). These CT features of mild COVID-19 are relatively difficult to distinguish from cryptogenic organizing pneumonia or secondary organizing pneumonia patterns from other causes, such as influenza pneumonia (16,48,58,60–62,65,66), reminding us that the organizing pneumonia pattern is not specific to COVID-19 and is a general response to lung injury (67).

Figure 4:

Representative CT images in mild and resolving COVID-19 pneumonia resembling organizing pneumonia. (A–C) Axial noncontrast CT images in a 65-year-old man with mild and reversible COVID-19 show peripheral and perilobular distribution of ground-glass opacities (dotted outlines) and the reversed halo sign (arrowhead), as well as vascular engorgement (arrow).

Radiology-Pathology Correlations in Moderate to Severe Progressing COVID-19

In moderate to severe COVID-19, the inflammatory cascade disrupts the alveolar-vascular basement membrane, putting patients at risk for progression to ARDS (52,56,57). In pathologic examinations, exudative-phase diffuse alveolar damage is most frequently reported in patients with potentially fatal COVID-19 (up to 88%), followed by proliferative- to fibrotic-phase diffuse alveolar damage and acute fibrinous organizing pneumonia (53). However, the high proportion of diffuse alveolar damage is not exclusive to fatal COVID-19, and similar proportions have been observed in severe acute respiratory syndrome and H1N1 influenza (53). Exudative-phase diffuse alveolar damage in severe COVID-19 is characterized by hyaline membrane formation from fibrin polymerization in the plasma liquid that has leaked into the interstitial and intra-alveolar space with alveolar edema, red blood cell extravasation, and intra-alveolar inflammatory cell infiltration (eg, neutrophils) (56,57). The proliferative and fibrotic phases of diffuse alveolar damage consist of intense fibroblast and myofibroblast recruitment and proliferation with subsequent extracellular matrix deposition, resulting in parenchymal remodeling and pulmonary fibrosis. Other characteristics of these late phases include pneumocyte squamous metaplasia, the presence of multinucleated giant cells, and thrombosis in small pulmonary arteries (1–2 mm in diameter), as is discussed later for endothelial injuries in COVID-19 (50,56,57). The pathologic abnormalities mentioned earlier were primarily based on autopsy specimens in a limited number of fatal cases and may not represent the full spectrum of severe COVID-19 pneumonia, particularly when different abnormalities—such as organizing pneumonia, acute fibrinous organizing pneumonia, diffuse alveolar damage, and superimposed infection other than COVID-19—coexist in the same patient (53,68).

Even in patients with moderate to severe disease courses, GGOs and consolidation are the major CT findings of COVID-19 (69). However, unlike the pathologic findings of GGO and consolidations in mild COVID-19, diffuse alveolar damage or acute fibrinous organizing pneumonia with or without vascular damage and thrombosis is the main histopathologic manifestation of severe COVID-19 (53,68,70) (Figs 5, 6). For example, GGOs are more frequently found in exudative-phase diffuse alveolar damage, and consolidations are more frequently found in proliferative- to fibrotic-phase diffuse alveolar damage or in acute fibrinous organizing pneumonia (29,48,68,70–72). In addition, GGOs and consolidations pronounced in the dependent portion of the lungs, sparing of the secondary lobules, and findings of fibrosis (eg, reticulation, traction bronchiectasis, and volume loss) are characteristic CT findings in the proliferative and fibrotic phases (48,69,73). Aside from diffuse alveolar damage and acute fibrinous organizing pneumonia, vascular damage with or without thrombosis, capillary dilatation and congestion, interstitial edema, and bronchopneumonia can contribute to extensive parenchymal opacifications (68,70).

Figure 5:

Radiologic and histopathologic findings of severe and fatal COVID-19 in a 62-year-old woman necessitating lung transplant due to acute respiratory distress syndrome. Specimens were stained with hematoxylin and eosin. (A) Axial, contrast-enhanced, preoperative chest CT image shows subpleural consolidation in the right upper lobe (dotted outline). (B) On a scan view of the extracted specimen of the right upper lobe, diffuse fibrotic lung parenchyma (*) with distorted bronchiole (arrows) was observed (scale bar: 2 mm; magnification: ×4). (C) With magnification (×10), destroyed lung parenchyma with microscopic honeycomb changes (*), fibroblastic proliferation, and some inflammatory cell infiltration (arrows) are observed, consistent with the proliferative to the fibrotic phase of diffuse alveolar damage (scale bar: 200 μm). (D) There is a fibrin thrombus with early organization in a medium-sized vessel (*) (scale bar: 100 μm; magnification: ×20). (E) Axial contrast-enhanced preoperative chest CT image shows a subpleural ground-glass opacity in the right upper lobe (dotted outline). (F) A low-power view of the extracted specimen of the right upper lobe visualizes the exudative phase of diffuse alveolar damage with mildly irregular interstitial thickening (arrows) (scale bar: 2 mm; magnification: ×4). (G) A high-power-field image shows focal denudation and reactive hyperplasia of pneumocytes, interstitial edema, and inflammatory cell infiltration, consistent with the exudative to proliferative phase of diffuse alveolar damage (arrows) (scale bar: 100 μm; magnification: ×20). (H) There are several microthrombi (arrows) and congestion in small pulmonary vessels and capillaries (scale bar: 100 μm; magnification: ×20).

Figure 6:

Another example of severe COVID-19 clinically manifesting as acute respiratory distress syndrome in a 66-year-old man undergoing bilateral lung transplant. Specimens were stained with hematoxylin and eosin. (A) Axial, contrast-enhanced, preoperative chest CT image shows consolidation and bronchiectasis in the right middle lobe (dotted outline). (B) On a scan view, diffuse subpleural, interstitial fibrosis and intrabronchiolar obstruction due to neutrophilic abscesses (*) are observed (scale bar: 2 mm; magnification: ×4). (C, D) With magnification (×10 in C and ×20 in D), a destroyed alveolar wall with fibrosis and type II pneumocyte hyperplasia are observed, and small foci of the proliferation of fibroblasts and myofibroblasts (arrows) is also seen, consistent with the proliferative to fibrotic phase of diffuse alveolar damage (scale bars: 200 μm in C and 100 μm in D). (E) Axial contrast-enhanced CT image shows subpleural ground-glass opacities in the right middle lobe (dotted outline). (F) A low-power view shows the exudative phase of diffuse alveolar damage with multifocal organizing pneumonia pattern (*) (scale bar: 2 mm; magnification: ×4). (G, H) High-power-field images show the typical features of acute fibrinous and organizing pneumonia: the presence of intra-alveolar fibrin filling the alveolar spaces (arrows), lymphoplasmacytic infiltration in the interstitium, and type II pneumocyte hyperplasia. Several microthrombi in small pulmonary vessels and capillaries with hemorrhage (*) are also observed (scale bar: 100 μm; magnification: ×20).

Summary Understanding of Lung Epithelial Injury in COVID-19

Lung epithelial injury in COVID-19 results from the direct toxicity of SARS-CoV-2 and the immune response depending on the host’s susceptibility to the virus (38–40). With alveolar-vascular basement membrane integrity as a key determinant, the histopathologic findings of COVID-19 pneumonia present a diverse spectrum encompassing nonspecific inflammation, organizing pneumonia, acute fibrinous organizing pneumonia, and diffuse alveolar damage as the general mechanisms of lung injury (48,53). Mild and reversible COVID-19 pneumonia pathologically represents nonspecific pneumonia to organizing pneumonia and radiologically manifests as predominant GGOs with small areas of consolidation resembling the organizing pneumonia pattern. In contrast, potentially fatal and irreversible COVID-19 pneumonia pathologically corresponds to diffuse alveolar damage or acute fibrinous organizing pneumonia with or without vascular abnormalities and radiologically manifests as extensive GGO and consolidations. Again, radiologic and pathologic findings can overlap between these two clinical courses of COVID-19 pneumonia and are not exclusive to each other. Fibrosis of postacute COVID-19 syndrome is beyond the scope of this article, and related information can be obtained from previous articles (74,75).

Endothelial Injury in COVID-19

The histopathologic findings of epithelial injury by SARS-CoV-2 are considered to be indistinguishable from those of other causes, such as influenza (76,77). Mounting evidence has suggested that pulmonary vascular endothelial injury, occurring along with the epithelial injury in the early disease course, is a nonspecific but prominent feature of COVID-19 (Fig 1, Table). Endothelial injury is a key factor for understanding the clinical course of COVID-19 and the pathogenesis of ARDS and multiorgan failure in COVID-19 (38,77–84). Indeed, several studies have reported patients with severe COVID-19 with hypoxemia but preserved lung compliance, suggesting that another process rather than alveolar damage exists, and endothelial injury is the center of attention for this type of hypoxemia (85,86). Endothelial damage in COVID-19 can occur in vessels of any size, from capillaries to large vessels, manifesting as endothelialitis, thromboemboli, pulmonary infarcts, perivascular inflammation, or intra-alveolar fibrin deposition by injured endothelial cells (53,78,79,83). For example, studies in the literature have reported pooled incidences of 57% for microthrombosis in the alveolar capillary vessels in COVID-19 pathologic samples and 12.8%–23.9% for venous thromboembolism, including 7.1%–16.5% of pulmonary thromboembolism and 11.2%–14.8% of deep vein thrombosis, which particularly increased to 22.7%–30.4% for venous thromboembolism in an intensive care unit (including 13.7%–24.7% for pulmonary thromboembolism) (25,53,79,87–89).

Pathologic Features of Endothelial Injury in COVID-19

As with epithelial injury, two hypotheses have been proposed regarding endothelial injury in potentially fatal COVID-19: direct viral cytopathic injury and indirect immune-mediated injury (83,90,91). Direct endothelial infection and subsequent injury induce endothelial permeability and the secretion of procoagulant factors (eg, plasminogen activator inhibitor 1) or vascular endothelial growth factors, resulting in ARDS and thrombotic complications, as well as angiogenesis (79,90,91). However, several studies have noted that the angiotensin-converting enzyme II receptor (the main SARS-CoV-2 cell surface receptor) is not expressed in endothelial cells at a significant level, and the endothelium is highly resistant to SARS-CoV-2 infection (90,92–96). Instead, an indirect mechanism involving impaired antithrombogenic properties of the endothelium and the activation of circulating prothrombotic factors by a self-amplifying cycle of excessive inflammation has been hypothesized (90,97,98). More specifically, viral infection of respiratory epithelial cells suppresses the interferon signaling pathway (eg, interferon type I/III), lowering viral clearance; then, a persistent high blood viral load upregulates the production of cytokines and chemokines (eg, interleukin 6 and tumor necrosis factor α) and activates the complement system (99–101). These mechanisms induce endothelial dysfunction and injury, continuing platelet aggregation and activation, vasoconstriction, and endothelial barrier disruption, eventually leading to pulmonary vessel inflammation, thrombosis, and transmigration to the alveolar space (102–104).

Radiologic Manifestations of Endothelial Injury in COVID-19

The distinct vascular abnormalities in COVID-19 can radiologically manifest as pulmonary thromboembolism, vessel engorgement, reduction of peripheral pulmonary blood vessels, a vascular tree-in-bud pattern, and lung perfusion abnormality.

Pulmonary Thromboembolism

Pulmonary thromboembolism is the principal manifestation of prothrombotic coagulation abnormalities in patients with COVID-19, contributing to morbidity and mortality (25,84,105) (Fig 7). A meta-analysis suggested that the pooled incidence of pulmonary thromboembolism and deep vein thrombosis is up to 16.5% and 14.8%, respectively (25). Greater disease severity, such as critically ill status or admission to the intensive care unit, was associated with a higher incidence of pulmonary thromboembolism (25). Intriguingly, only 42% of patients with pulmonary thromboembolism had deep vein thrombosis, and pulmonary thromboembolism was more frequently located in the peripheral arteries (60%) than in the central arteries (40%). These findings suggest the in situ formation of pulmonary thromboembolism, unlike the conventional inextricable relationship between pulmonary thromboembolism and deep vein thrombosis (25,106,107).

Figure 7:

Representative CT images of pulmonary thromboembolism in a 78-year-old man with COVID-19. (A–C) Axial CT images with contrast medium demonstrate pulmonary thromboembolism in the distal left lower lobar and segmental, left upper lingular segmental pulmonary arteries (arrowhead). (D) Axial contrast-enhanced lung window CT image shows the peripheral distribution of ground-glass opacities and consolidation bilaterally.

Pulmonary Vascular Engorgement

Several researchers have consistently reported pulmonary vascular engorgement from the early phase of the COVID-19 pandemic, with a prevalence of 69% in patients with COVID-19 (69,107,108) (Fig 4). Vascular engorgement (dilated or tortuous morphologic features) was typically observed in the segmental and subsegmental pulmonary arteries or arterioles of 5 mm² or larger. Engorged vessels usually pass through or around peripheral GGOs and are presumed to reflect alveolar septal capillary congestion by increased vascular permeability with subsequent edema of lung interstitium (109). Hypothetically, vascular engorgement is pathologically attributable to the vessel wall damage and edema caused by proinflammatory factors and to hyperemia of increased blood flow of the corresponding pulmonary vessels. These vascular changes can reflect the failure of physiologic hypoxic vasoconstriction caused by dysfunctional and diffuse inflammation or secondary vascular dilatation (ie, congestion) proximal to the SARS-CoV-2 affected microvessels due to microvascular thrombosis (56,88,89). In the clinical aspect, patients with COVID-19 with engorged pulmonary vessels have longer lengths of hospitalization and ventilation (107).

Reduction of Peripheral Pulmonary Blood Vessels

According to previous studies using automatic pulmonary vascular segmentation via Hounsfield unit thresholds or a deep learning–based approach, the pulmonary blood volume (BV) in vessels less than 5 mm² (ie, BV5; corresponding to a diameter of 1.25 mm) is reduced in patients with COVID-19, whereas the vascular volume is increased in vessels of 5–10 mm² (ie, BV5–10) and larger than 10 mm² (BV10) (110–113) (Fig 8). This reduction of the small peripheral vessels is presumed to result from virus-induced microcirculatory disruption, increasing vascular resistance by dysregulated vasoconstriction or vessel occlusion by microthrombi or tissue damage (110–113). In terms of prognosis for patients with COVID-19, the BV5%, calculated as the proportion of total BV in BV5, was found to be a prognostic factor predicting adverse outcomes (intubation or mortality) in patients with COVID-19 (112). In a recent study, the Omicron variant had a higher BV5% than the Delta variant, suggesting less pulmonary vascular involvement for the Omicron variant (114). Although this reduction in BV5 was larger in patients with COVID-19 than in patients with conventional ARDS and healthy individuals, this is not an exclusive feature of COVID-19 and can be observed in other diseases, including influenza pneumonia, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma (112,113,115,116). In line with this notion, sublingual vascular density representing splanchnic microvasculature significantly decreased by up to 90% in patients with COVID-19 (117), exclusively limited to tiny capillaries (diameter of 4–6 μm) in critically ill patients (118,119).

Figure 8:

Different peripheral pulmonary vascularity and disease courses in two older patients of similar ages. The blue vessels have a cross-sectional area of 5 mm² or larger, while the yellow vessels have a cross-sectional area under 5 mm². (A, B) Representative three-dimensional images in an 80-year-old man with hypertension show lower lobe–predominant pneumonia (red; pneumonia volume, 3.9%) and a preserved percentage of blood volume (BV) in intrapulmonary vessels with a cross-sectional area of less than 5 mm² relative to the total pulmonary BV (51.3%). (C, D) Representative three-dimensional images in a 79-year-old man with hypertension and diabetes show larger lower lobe–predominant pneumonia (red; pneumonia volume, 28.4%) and a lower percentage of BV in intrapulmonary vessels with a cross-sectional area under 5 mm² relative to the total pulmonary BV (31.8%). The latter patient died of COVID-19, while the former patient recovered.

Vascular Tree-in-Bud Pattern

The tree-in-bud pattern at CT is conventionally used to describe infectious conditions extending along the airways and is acknowledged as an atypical CT appearance in the RSNA classification (16). Although a few studies reported this pattern in tumor thrombosis, Patel et al first introduced the vascular tree-in-bud pattern in severe COVID-19 as a characteristic pattern (107) (Fig 9). Peripheral pulmonary vessels accentuated by the COVID-19 vasculopathy of hypercoagulability, with reduced fibrinolytic capacity and resultant microthrombosis, are assumed to be demonstrated as the vascular tree-in-bud pattern at CT (77,79,107). However, direct radiologic-pathologic matching remains underexplored (77). Interestingly, this CT finding was found to be correlated with longer ventilation and hospitalization in patients with COVID-19, highlighting its prognostic role (77,107).

Figure 9:

Representative axial contrast-enhanced CT images of the vascular tree-in-bud pattern in patients with COVID-19. (A, B) CT images in a 71-year-old man with COVID-19 show accentuated peripheral pulmonary vessels in the right upper lobe (arrowhead in A and arrows in B, magnified). (C, D) CT images shows the vascular tree-in-bud pattern in a 54-year-old man with COVID-19 (arrowhead in C and arrows in D, magnified).

The vascular tree-in-bud pattern reflects an increase in peripheral BV and may seem to contradict the aforementioned reduction of BV5 (110–113). However, the vascular tree-in-bud pattern is a focal radiologic manifestation, whereas the analysis of vascular volume in BV5 deals with the entire pulmonary vasculature. Accordingly, even if the vascular tree-in-bud pattern exists focally, it may not significantly affect the overall pulmonary peripheral vascularity. Further research on a direct radiologic-pathologic comparison for this CT pattern will clarify this heretofore unsolved issue.

Lung Perfusion Abnormality

Abnormal lung perfusion is frequently reported at dual-energy CT in COVID-19 (85,107) (Fig 10). Abnormal perfusion manifests as various shapes, including wedge, mottled, or mixed patterns, and varied perfusion patterns, including oligemia corresponding to lung opacity area and peri-opacity hyperemia (85,107). This abnormal perfusion in COVID-19 is frequently accompanied by proximal and distal pulmonary vessel engorgement, predominantly within or surrounding lung opacity areas, presumptively from the failure of physiologic hypoxic pulmonary vasoconstriction (85). Abnormal lung perfusion is apparent separately from pulmonary emboli and airway abnormalities, and the hypothetical causes are also hypoxic vasoconstriction, microthrombi, or decreased capillaries (25,85). Clinically, lung perfusion abnormality has been associated with ventilation-perfusion mismatch and hypoxia (85).

Figure 10:

Lung perfusion abnormality in COVID-19. (A, B) Axial contrast-enhanced dual-energy perfusion CT images in an 83-year-old man confirmed to have COVID-19 show a peripheral distribution of ground-glass opacities and consolidations in the lower lobes of the bilateral lungs without evidence of pulmonary thromboembolism. (C) Perfusion map demonstrates perilesional hyperemia (arrowheads) and lesional oligemia (arrow). Color bar shows lung perfusion degree; dark and bright colors mean low and high perfusion, respectively.

Airway Injury in COVID-19

Airway injuries and changes have been discussed less frequently than alveolar epithelial or endothelial injuries in COVID-19, but several radiologic studies have reported bronchiectasis and bronchial wall thickening in 10%–20% of patients with COVID-19, especially in critically ill patients (120–123). For patients with persistent symptoms, such as postacute sequelae of COVID-19, significant air trapping observed at CT was reported in 25%–35% of the total lung volume (124). The proportion of air trapping was not different according to the initial disease severity but was significantly higher than that of healthy controls (124). Because the angiotensin-converting enzyme II receptor is expressed throughout the airway tract, including the small airway, it is speculated that the virus directly infects and injures the airway, resulting in functional small airway disease involving air trapping (124). The exact pathophysiologic process underlying SARS-CoV-2–induced air trapping is not yet determined. However, a study reporting fibrogranulation tissue proliferation in small airways and subpleural airspaces in patients with severe acute respiratory syndrome hints at this airway abnormality (125). In addition, the immune response provoking postinfectious bronchiolitis obliterans in other severe viral diseases has been speculated to be another mechanism for this small airway abnormality (124).

Clinical Implications of Epithelial and Endothelial Injuries Caused by COVID-19

Both epithelial and endothelial injuries in COVID-19, as described earlier, simultaneously but independently occur as a result of direct viral infection and indirect immunopathologic effects. For epithelial injury, the intact alveolar-vascular basement membrane is paramount in determining whether the organization by lung injury is resolved and reversible (typically represented as the organizing pneumonia pattern) or lung injury continues to diffuse alveolar damage, clinically manifesting as ARDS. Regarding endothelial injury, several CT examinations can be used to detect and specify various manifestations of COVID-19 pulmonary vasculopathy in pulmonary vessels of different calibers: endothelialitis, vasoconstriction, microthrombi, and decreased capillaries in peripheral subsegmental arteries can be depicted using CT quantification techniques (eg, BV5) or dual-energy perfusion CT (eg, lesional oligemia and perilesional hyperemia). Moreover, vessel engorgement and pulmonary thromboembolism in segmental to large arteries can be easily detected at conventional CT with contrast medium.

Regarding epithelial injuries, CT findings alone cannot render specific pathologic findings but can reflect whether mild reversible versus severe progressing abnormalities are more likely to occur. For example, severe progressing COVID-19 pneumonia can involve lung parenchyma more extensively than mild resolving pneumonia. Thanks to the ability of the imaging modalities to depict the extent of parenchyma affected by SARS-CoV-2, severity scoring using radiographs and CT correlate with outcomes such as hospitalization, intensive care unit admission, mechanical ventilation, and mortality (126,127). Furthermore, with recent rapid advances, artificial intelligence is applied for COVID-19 pneumonia in various clinical tasks, including quantifying pneumonia extent in serial chest CT, detecting differences in CT findings between variants, measuring pulmonary disease severity at chest imaging, and predicting patient prognosis (114,128–131). The results of the artificial intelligence approaches are potentially promising in detecting clinically relevant changes in COVID-19 pneumonia and triaging patients in a real-world clinical setting.

From a therapeutic perspective, chest CT can be helpful in the management of patients with COVID-19 by providing information on epithelial or endothelial injuries. In the phase of viral replications, therapies such as antiviral drugs (eg, remdesivir) that interfere with viral replication can effectively truncate disease progression and hasten the improvement of COVID-19 by decreasing the viral load (40,132). If severe inflammation has already occurred, anti-inflammatory agents such as dexamethasone can help reduce mortality in patients with severe COVID-19 (40,133). In addition, antifibrotic agents can be administrated for patients with a CT pattern of fibrosis adjudicated as irreversible, even though their use has been reported only in case reports or series (134,135). Finally, if COVID-19 vasculopathy is evident at CT, anticoagulants and anticomplement agents are indicated (25,83). Accompanied by this therapeutic view, prognostication of patients with COVID-19 can also be achieved based on the chest imaging findings of alveolar epithelial and endothelial injuries. This integrated perspective on the radiologic and pathologic findings of COVID-19 can facilitate timely and appropriate treatment strategies.

An important point that should be considered is that representative CT findings and imaging severity of COVID-19 change as the dominant strain of SARS-CoV-2 changes (5,114). For example, the Omicron variant, the latest variant of concern, showed more frequent negative CT abnormalities and atypical pattern of COVID-19 pneumonia, including fewer and less severe lung parenchymal changes and pulmonary vascular involvement but a greater peribronchovascular predilection and bronchial wall thickening than the Delta variant, and these CT patterns correlated with improved hospital outcomes in patients with the Omicron variant (5,114). The frequent atypical pattern in the Omicron variant may be associated with changing cellular tropism and efficient replication of SARS-CoV-2 toward bronchial tissue rather than lung parenchyma (4,136).

Conclusion

In COVID-19, chest imaging findings reflect pathologic changes beyond an anatomic resolution. Mild COVID-19 pneumonia manifests as ground-glass opacity–dominant lesions involving a relatively limited extent, which are pathologically reflected in the organizing pneumonia pattern or nonspecific bronchopneumonia. Potentially fatal COVID-19 pneumonia commonly manifests as more extensive mixed to consolidation-dominant lesions, pathologically representing diffuse alveolar damage or acute fibrinous organizing pneumonia patterns. Although chest imaging cannot directly depict the integrity of the alveolar-vascular basement membrane, imaging features can help stratify the disease course of COVID-19 to determine whether it can be reversed or will progress irreversibly. In addition to epithelial injury in COVID-19, endothelial injury is characteristically considered a major cause of acute respiratory distress syndrome. Modern advanced CT imaging can demonstrate various manifestations of these epithelial and endothelial injuries in COVID-19 and help narrow differential diagnoses, identify patients at risk for deterioration, prognosticate COVID-19 pneumonia, and promptly figure out the pathophysiologic characteristics of the future respiratory tract–related pandemic when it occurs.