Pulmonary Vascular Manifestations of COVID-19 Pneumonia

Introduction

Since December 2019, infection by novel coronavirus severe acute respiratory syndrome coronavirus 2 has erupted into a global pandemic, with more than 2.3 million reported cases worldwide to date (1). The parenchymal imaging findings of coronavirus disease 2019 (COVID-19) pneumonia have been well described, including multifocal peripheral ground-glass opacities with or without consolidation (2–5). However, these findings are not specific and can be seen in various other diseases, including other viral pneumonias, atypical bacterial pneumonia, drug toxicity, eosinophilic pneumonia, or cryptogenic organizing pneumonia (3,6–8).

Progression to acute respiratory distress syndrome (ARDS) has been reported in 20% of COVID-19 pneumonia cases and in up to 41% of patients who are hospitalized (9). However, some patients requiring intubation have relatively preserved lung compliance, suggesting involvement of other processes in addition to parenchymal damage. Recent studies have proposed that loss of perfusion regulation and loss of normal physiologic hypoxic vasoconstriction contribute to the hypoxemia seen in patients with COVID-19 (10,11). In addition, there has been increasing concern for hypercoagulability and pulmonary embolism (PE) in patients with COVID-19, with a few concordant autopsy studies reporting findings of pulmonary microthrombi (12–17). Finally, regional and diffuse pulmonary vascular pathology has also been suggested, including conditions mimicking high-altitude pulmonary edema (18). Consistent with vascular pathology playing an important role in the pathophysiology of COVID-19 pneumonia, prior reports did note a high prevalence of vessel enlargement and thickening within areas of pulmonary parenchymal opacity in patients with COVID-19 (2,4,5). However, to our knowledge, a detailed investigation of pulmonary vascular findings at CT is lacking in the literature.

Recently, we observed perfusion abnormalities in several patients with COVID-19 infection who underwent dual energy CT (DECT) imaging for suspicion of PE (19). These perfusion changes further support an underlying vascular pathology, but systematic investigation of its manifestation in COVID-19 pneumonia has not been described. Our goal was to assess pulmonary vascular findings at CT, including the prevalence of PE in our cohort, abnormalities of pulmonary vessels, and mosaic attenuation. In addition, we used DECT, available on a subset of our scanners, to obtain pulmonary blood volume images and assess lung perfusion patterns in COVID-19 pneumonia.

Materials and Methods

Results

A total of 48 patients were included in this retrospective study. The average age was 58 years ± 19, and 23 patients (48%) were women (Table 1). The most common manifesting symptoms included cough (71%), fever (60%), and shortness of breath (58%). Hypertension (48%), obesity (44%), history of malignancy (23%), and diabetes (19%) were the four most prevalent comorbidities. No patients had prior liver disease. Only two (4%) patients had a pre-existing pulmonary condition of chronic obstructive pulmonary disease. Six (13%) patients had a history of PE. Forty-five patients (94%) required admission, with 18 patients (38%) requiring admission to the intensive care unit. Thirty-five patients (73%) required nasal cannula to maintain oxygen saturation above 90% during admission, with 13 (27%) of these patients eventually requiring intubation. At the date of last follow-up, 14 patients were discharged (29%), and two patients who required intubation were deceased (4%).

Table 1: Summary of Patient Characteristics

Consistent with previous reports, the most common features seen at chest CT of patients with COVID-19 are multilobar ground-glass opacities with or without consolidation in a predominantly peripheral distribution (Table 2); of note, the distribution was assessed in 44 cases, as four studies were categorized as negative for pneumonia without evidence of opacity. The average severity scores of individual lobes are listed in Table 2 and were significantly different between the lobes (P = .03), with both lower lobes having a higher average severity score (average left lower lobe severity score of 1.9 of 3, and average right lower lobe severity score 2 of 3) than the other lobes (range 1.3–1.7 of 3) (Table 2). On the basis of the RSNA/STR/ACR consensus guidelines, the findings were classified as typical in 56% of cases, indeterminate in 23%, atypical in 13%, and negative for pneumonia in 8% (Table 2).

Table 2: Pulmonary Opacities at Chest CT

A total of seven patients (15%) were found to have PE (Fig E1 [supplement]), with six cases (13%) involving arteries of multiple lobes, three cases (6%) exhibiting pulmonary infarcts, and one case (2%) with evidence of right heart strain (Table 3) (22). Two of the seven patients with PE were admitted to the intensive care unit and did not require intubation. Main pulmonary artery dilatation (23) (≥ 30 mm) was observed in eight patients (17%) (24). Patients with PE had on average significantly higher ᴅ-dimer levels than patients without PE (6136 ng/mL ± 3951 vs 3653 ng/mL ± 1439, respectively; P = .02) (Table 3).

Table 3: Vascular and Perfusion Findings

Overall, dilated pulmonary vasculature was seen in 41 (85%) cases, with 38 (79%) within pulmonary opacities and 27 (56%) outside of the opacities (Table 3; Figs 1, A, 2, 3, C), and dilated distal pulmonary vessels extending to the pleura and fissures were seen in 40 cases (83%) and 30 cases (63%), respectively (Figs 4 A and B, 5). As described, vascular enlargement was often within or outside the opacity and extended to the pleura generally near ground-glass opacities without diffuse involvement. Ten of our patients had chest CT imaging available that was performed within 6 months prior to COVID-19 infection, and none of the vascular findings or evidence of pulmonary hypertension were observed previously. Mosaic attenuation, likely from mosaic perfusion, was noted in 45 cases (94%) at conventional chest CT lung window (−500 to 1000 Hounsfield units). Dilated pulmonary vessels even outside of vessels with emboli were seen in five of seven patients with PE.

Figure 1:

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Figure 2:

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Figure 3:

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Figure 4:

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Figure 5:

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Overall, DECT was performed in 25 cases (52%). A mosaic perfusion pattern was observed in 24 cases (96%), with one (4%) categorized as mild, 17 (68%) as moderate, and six (24%) as severe (Table 3; Figs 1, B and D, 2, B and D, 3, B and D). More specifically, regionally increased hyperemia overlapping with areas of pulmonary opacities or immediately surrounding the opacities were seen in 13 cases (52%). Pulmonary opacities associated with corresponding oligemia at DECT were observed in 24 cases (96%). Intensely hyperemic area surrounding oligemic pulmonary opacities forming a peripheral hyperemic halo was noted in nine cases (36%). Of note, all seven patients with PE exhibited perfusion abnormalities at DECT: Seven had mosaic perfusion, four had hyperemia overlapping with areas of pulmonary opacities, seven had oligemia, and four had hyperemic halo. Figure E2 (supplement) provides a reference of normal conventional chest CT and DECT images in a patient with COVID-19 infection but without respiratory symptoms and without lung parenchymal abnormalities at imaging; CT pulmonary angiogram was obtained for chest pain, tachycardia, and elevated d-dimer. Finally, of the 25 patients who underwent DECT, perfusion abnormalities were seen in all patients who required intubation or were deceased (four of four patients) and in 95% of patients who did not require intubation (20 of 21 patients).

Discussion

The pulmonary response to pneumonia is generally characterized by hypoxic pulmonary vasoconstriction and reduced perfusion to the sites of parenchymal disease, resulting in shunting of blood away from most affected and toward less affected regions–a beneficial matching of ventilation and perfusion (25). Our finding of frequent and pronounced dilatation of vasculature to regions of diseased lung may be suggestive of disordered vasoregulation, leading to substantial ventilation and perfusion mismatch even early in the disease. This finding may explain in part the hypoxemia that can occur in COVID-19 pneumonia despite normal pulmonary compliance (10,11). Although attention has been previously given to the role of endothelial damage and resulting dysregulation of hypoxic vasoconstriction in the setting of ARDS (26), we hypothesize that abnormal pulmonary vasoregulation may play a large role in patients with COVID-19 infection even before the presence of radiologic or clinical features that would suggest ARDS and may be even more pronounced when ARDS does occur.

In normal lung, distal subsegmental vessels are usually inconspicuous within the subpleural regions. A substantial number of patients in our study, however, exhibited dilated and sometimes tortuous distal vessels in the subpleural lung. This phenomenon is distinct from the pulmonary vascular thickening (or the “thick vessel sign”) within pulmonary opacities in COVID-19 pneumonia that has been reported to range from 59% to 82% in patients with COVID-19 (2,4,5). This finding is nonspecific and can be seen in conditions such as pulmonary hypertension, pulmonary venous hypertension, pulmonary veno-occlusive disease, hepatopulmonary syndrome, and portopulmonary hypertension (27). However, patients in this study with imaging prior to COVID-19 infection had none of these findings, which argues against a chronic process. Moreover, there was a lack of hepatic disease or other pre-existing pulmonary conditions that would provide a reason for the vascular pathology.

Diffuse alveolar damage is a hallmark of ARDS and can be caused by noninfectious etiologies and infectious etiologies, including viral pneumonia such as severe acute respiratory syndrome, Middle East respiratory syndrome, and influenza (28–32). Development of ARDS-related thrombosis was thought to be the result of fibrin deposition due to endothelial injury (33). A recent autopsy study on a series of patients with COVID-19 infection, however, reported not only findings of widespread macro- and microthrombosis, but also angiopathy and notably increased angiogenesis (34). Furthermore, in this recent report, fibrin thrombi were seen in all patients with COVID-19 infection, and angiogenesis was observed 2.7 times higher in patients with COVID-19 infection than those with influenza. While this provides additional validation of prior autopsy reports describing microthombosis and small vessel thickening in patients with COVID-19 pneumonia, it also provides evidence of more widespread vascular pathologies, such as angiogenesis and endothelial inflammation. These vascular mechanisms also appear to play a larger role in COVID-19 pneumonia than other viral pneumonias such as influenza (34). The vascular abnormalities we observed at CT imaging correlate well with these pathology findings and support the notion of diffuse vascular abnormalities in COVID-19 pneumonia. The underlying mechanisms of these findings, however, may be related to vascular inflammation, endothelial damage, microthrombosis, dysfunctional vasoregulation, or a combination thereof (10,30,34–38). Further radiologic-pathologic correlation investigations are needed to better elucidate the underlying vascular phenomenon.

DECT is a powerful imaging tool used to characterize pulmonary blood volume and patterns of pulmonary perfusion by taking advantage of the different attenuation profiles of different substances (39,40). This is achieved by utilizing two different x-ray energy spectra concurrently during imaging. DECT is part of the standard PE CT protocol at a subset of hospitals within our health care system. In the COVID-19 setting, DECT may provide insight into the physiologic process of vascular shunting. Of the 25 patients who underwent DECT in our study, mosaic perfusion abnormalities were seen in 24 patients (96%), with predominately increased perfusion proximal to areas of lung opacities. Mosaic perfusion is a subset of mosaic attenuation and can be broadly categorized into two etiologic categories: small airway disease with hypoxemic vasoconstriction due to air trapping, or small vessel disease (40,41). While mosaic attenuation and perfusion can be seen in infections because of diffuse airway abnormalities and/or mucus plugging, the perfusion changes in our patients did not correlate in most cases with bronchial wall thickening, visible secretions, mucous plugging, or emphysema, arguing against small airway disease as a sole or primary underlying cause. Furthermore, the perfusion abnormalities had a regional rather than lobular distribution and extended beyond areas of parenchymal lung opacity, suggesting the possibility of a diffuse vascular process.

There were decreased areas of peripheral perfusion corresponding to peripheral lung opacities in 24 of 25 patients who underwent DECT (96%). This radiographic observation can be consistent with ARDS, as areas of oligemia can be seen in ARDS-related thrombosis (33). The opacities with corresponding decreased perfusion may represent filling of airspaces and interstitium with exudates, or possibly peripheral areas of infarction mediated by small vessel thrombosis. Furthermore, of the 25 patients who underwent DECT, perfusion abnormalities were observed in all patients who required intubation or were deceased and in 95% of patients who did not require intubation. This suggests that perfusion abnormalities are highly prevalent in symptomatic patients who required admission. The small number of patients who underwent DECT, however, limited meaningful correlation of these findings to degree of hypoxemia or clinical outcome, which will require further investigation. Interestingly, however, there was a peripheral halo of increased perfusion surrounding peripheral opacities in nine patients (36%). This appearance is not typical in ARDS or acute or chronic PE, in which uniformly decreased perfusion is seen within affected areas. The peripheral halo of increased perfusion observed in our study has neither been described in the literature nor noted in our practice in cases of pulmonary infarction due to bland PE but has been described once previously in a case of bacterial pneumonia (40). This suggests an interplay between inflammatory processes and vascular phenomena in a subset of COVID-19 pneumonia. Further research into whether DECT may provide prognostic information for patients with COVID-19 is needed.

There are multiple possible causes of differential pulmonary perfusion. PE, pulmonary hypertension, and vasculitis are additional conditions that can alter pulmonary perfusion (42). PE and pulmonary hypertension as the primary underlying causes of mosaic perfusion in our cohort of patients with COVID-19 pneumonia are unlikely given that perfusion abnormalities were seen in patients without visible PE and often did not correspond to areas supplied by the pulmonary arteries containing thrombus; furthermore, our patients did not have a history of pulmonary hypertension, and only a small proportion of patients exhibited a mildly dilated main pulmonary artery (17%). Vasculitis secondary to infection can have varying appearances at imaging, including vessel wall thickening, cavitary lesions, and ground-glass or consolidative opacities (43). However, it would be unusual for isolated involvement of medium-to-small pulmonary vessels, and there is a lack of concordant findings reported on pathology (13,16).

There has been suggestion that the pathophysiology underlying COVID-19 pneumonia may resemble high-altitude pulmonary edema (18). While there are imaging similarities, including patchy ground-glass opacities, dilated vasculature, and regional perfusion changes (44–46), the fundamental mechanism may be different, as COVID-19 is likely inflammation mediated, whereas high-altitude pulmonary edema is characterized by uneven pulmonary vasoconstriction, increased pulmonary artery pressure, and endothelial leakage (47). Abnormal inflammation-mediated vasodilatory response in COVID-19 pneumonia may result in intrapulmonary shunting toward areas of impaired gas exchange and worsening of ventilation-perfusion mismatch, possibly explaining the enlarged vessels leading to and within areas of parenchymal opacity seen in our study.

The theory that patients with COVID-19 are at higher risk of both venous and arterial thrombosis has also recently garnered attention. The reported risk of venous thromboembolism in patients with COVID-19 has been reported to range from 25% to 31% (12,14). The incidence of PE specifically has been reported to range from 14% to 30% (12,15,48–50). Similarly, seven patients (15%) in our study were found to have PE, four of whom had risk factors including history of arrhythmia, malignancy, or prior PE or deep vein thrombosis. Acute PE, therefore, may be a potential concern in patients with COVID-19, similar to other viral pneumonias and critically ill patients in general (51–53). In addition to medium-to-large vessel thrombosis, a handful of autopsy reports of COVID-19 have reported findings of microthrombosis and small vessel thickening, which can be seen in the setting of ARDS, coagulopathies, and other etiologies of vessel injury (13,16,54).

Our study had several limitations. The study was retrospective, and the patient cohort size was relatively small given our inclusion criteria of COVID-19 patients who underwent CT-PE during a 2-week window. Most patients in the study did not have a recent prior chest CT that would allow us to assess the temporal development of imaging findings, and it is possible that some of the vascular abnormalities predated the CT scans obtained during the acute illness. Many of the findings we detected were nonspecific and can occur in other diseases, and our study was not designed to assess the specificity of the findings for COVID-19 pneumonia. DECT images were only available for 25 patients due to availability of scanners at different hospitals across our health care system, and inspiratory and expiratory phases were not performed as part of the standard imaging protocol, which may potentially confound mosaic patterns seen on CT images. Our study was also limited by the lack of control groups: patients without COVID-19 infection or those with COVID-19 infection but who did not require admission. Future studies with matched control groups, as well as patients with other appropriate pathologies, including organizing pneumonia and influenza, would be helpful to further clarify the extent of these vascular findings. Finally, assessment of vessel enlargement and mosaic perfusion can be subjective and therefore requires further confirmation with larger multireader studies or quantitative methods of categorization.

In conclusion, COVID-19 pneumonia appears to be associated with pulmonary vascular and pulmonary perfusion derangements that are caused by unclear mechanisms. Pulmonary vessel dilatation occurs not only within lung opacities, but also occurs in a regional pattern outside of parenchymal opacities and sometimes involves the subpleural lung. Perfusion abnormalities are also frequently seen at DECT imaging. Further imaging and pathologic studies are required to investigate the possible contributions of abnormal vasoregulation, intrapulmonary shunting, and/or microvascular thrombosis.