key: cord-0785628-f9ypcl3y
authors: von der Thüsen, Jan H.; Ghariq, Elyas; Overbeek, Maria J.; Leyten, Eliane; Drijkoningen, Tessa; Gietema, Hester A.; Prokop, Mathias; Quarles van Ufford, Henriette M. E.
title: Spectrum of Vascular Involvement in Coronavirus Disease 2019 Pneumonia—Findings on CT Perfusion
date: 2020-10-21
journal: Crit Care Explor
DOI: 10.1097/cce.0000000000000266
sha: 019795ddcba55557e3615641affd5a1c0e67d45a
doc_id: 785628
cord_uid: f9ypcl3y

OBJECTIVES: There is accumulating evidence of a distinct coagulopathy in severe acute respiratory syndrome coronavirus 2 infection which is associated with poor prognosis in coronavirus disease 2019. Coagulation abnormalities in blood samples resemble systemic coagulopathies in other severe infections but demonstrate specific features such as a very high d-dimer. These clinical observations are consistent with histopathologic findings of locally disturbed pulmonary microvascular thrombosis and angiopathy in end-stage coronavirus disease 2019. However, exact underlying processes and the sequence of events are not fully understood. DATA SOURCES: CT perfusion may provide insight in the dynamic aspect of the vascularity in pulmonary lesions in coronavirus disease 2019 infection as, in contrast to dual energy CT, a multiphase perfusion pattern is displayed. STUDY SELECTION: In six patients with coronavirus disease 2019 pneumonia, findings on additional CT perfusion series were correlated with known histopathologic vascular patterns upon pulmonary autopsy of patients who had died of coronavirus disease 2019. DATA EXTRACTION: In this case series, we were able to show perfusion changes on CT scans in typical pulmonary lesions illustrating diverse patterns. DATA SYNTHESIS: We demonstrated hyperperfusion in areas with ground glass and a severely decreased perfusion pattern in more consolidated areas often seen later in the course of disease. A combination was also observed, illustrating temporal heterogeneity. CONCLUSIONS: These findings provide new insights into the pathophysiology of coronavirus disease 2019 pneumonia and further understanding of the mechanisms that lead to respiratory failure in these patients.

Objectives: There is accumulating evidence of a distinct coagulopathy in severe acute respiratory syndrome coronavirus 2 infection which is associated with poor prognosis in coronavirus disease 2019. Coagulation abnormalities in blood samples resemble systemic coagulopathies in other severe infections but demonstrate specific features such as a very high d-dimer. These clinical observations are consistent with histopathologic findings of locally disturbed pulmonary microvascular thrombosis and angiopathy in end-stage coronavirus disease 2019. However, exact underlying processes and the sequence of events are not fully understood. Data Sources: CT perfusion may provide insight in the dynamic aspect of the vascularity in pulmonary lesions in coronavirus disease 2019 infection as, in contrast to dual energy CT, a multiphase perfusion pattern is displayed. Study Selection: In six patients with coronavirus disease 2019 pneumonia, findings on additional CT perfusion series were correlated with known histopathologic vascular patterns upon pulmonary autopsy of patients who had died of coronavirus disease 2019. Data Extraction: In this case series, we were able to show perfusion changes on CT scans in typical pulmonary lesions illustrating diverse patterns.

Data Synthesis: We demonstrated hyperperfusion in areas with ground glass and a severely decreased perfusion pattern in more consolidated areas often seen later in the course of disease. A combination was also observed, illustrating temporal heterogeneity. Conclusions: These findings provide new insights into the pathophysiology of coronavirus disease 2019 pneumonia and further understanding of the mechanisms that lead to respiratory failure in these patients. (1) (2) (3) (4) . These clinical observations are consistent with histopathologic findings of microvascular thrombosis and angiopathy in endstage COVID-19 lung (5) . However, the precise pathophysiology and pathobiology is not fully understood.

Typical findings on chest CT in COVID-19 pneumonia include ground glass opacities with multifocal bilateral distribution in regions close to visceral pleural surfaces (6, 7) . Dilated vessels (> 3 mm diameter) entering ground glass opacities is another characteristic finding, interpreted as a thromboinflammatory process (2, 6) . CT perfusion (CTP) may provide insight in the dynamic aspect of the vascularity in pulmonary lesions in COVID-19 infection as, in contrast to dual energy CT, a multiphase perfusion pattern is displayed (8) . Therefore, CTP series may improve understanding of pathophysiologic mechanisms in developing thromboembolic and microvascular thrombotic complications.

In this article, we observe and interpret CTP patterns of COVID-19 pulmonary features. To improve understanding of CTP patterns and underlying pathophysiology, results are correlated with known histopathologic vascular patterns in autopsy cases with COVID-19 pneumonia (9).

www.ccejournal.org 2020 • Volume 2 • e0266

Six patients with COVID-19 pneumonia in different disease stages were retrospectively studied. Because of suspected pulmonary thromboembolic complications, CT angiography (CTA) was performed with additional CTP series. All patients signed consent for the use of their data for this study, and all data were acquired in the context of routine patient care. A formal study protocol was not required, following waiver by the institutional review board (reg. no G20.080). CTP was performed in an 8.5 cm thick slab placed at most prominent pathologic areas accessible for evaluation, including the aorta, pulmonary artery, left ventricle, and normal lung parenchyma for postprocessing. The sequential low-dose acquisition of this slab was performed after injection of 40 mL iodinated contrast at 5 mL/s. Postprocessing was done using dual-input 4D lung perfusion on a Vitrea dedicated workstation (Vitrea; Canon Medical Systems, Otawara, Japan). Perfusion maps were reconstructed using systemic arterial flow (AF) via the bronchial arteries and pulmonary artery flow (PF) (in mL/[min/100 mL]). Hypo-and hyperperfusion were defined relative to morphologically normal lung parenchyma. Perfusion patterns were described as PF/AF pairs: double hyperperfusion if for both PF and AF, hyperperfusion was present in the affected area, mixed perfusion if PF was reduced but AF was increased, and double hypoperfusion if both PF and AF were reduced. The observations on CTP were put in relation to CTA findings and previous scans, if available.

CT findings in lung parenchyma were classified as low-density ground glass opacity in opacities with an attenuation less than -600 Hounsfield Units (HU), and high-density ground glass opacity with an attenuation of at least -250 HU. We also analyzed crazy paving (ground glass opacities with reticulation) and consolidations.

Direct correlation of CT patterns and histopathologic findings in COVID-19 is difficult. We used the combination of morphologic CT and CTP findings to find corresponding histopathologic patterns in lung tissue from four patients who had died of COVID-19 pneumonia that could explain the CT phenotypes.

We included six patients with reverse transcription polymerase chain reaction-proven COVID-19 infection; median age 62.6 years (range 43-73 yr) and median duration of symptoms at time of CTP 16.2 days (range 4-29 d).

On CTP, we found three distinct perfusion patterns in COVID-19 lesions. A double hyperperfusion pattern, via the bronchial arteries, was seen in areas of low-density ground glass opacities (Fig. 1, first column) and present in all six patients. The affected regions showed dilated vessels entering the ground glass opacities. These vessels were patent and well-opacified on CTA (Fig. 2) .

Histopathologic findings corresponding to this pattern may be dilated pulmonary arteries in regions with microvascular dilation in the context of acute interstitial pneumonia (Fig. 1, first column) .

A double hypoperfusion pattern was seen in five patients (Fig. 1, second and third columns) . This pattern was present in this series past day 10. It occurred in dense ground glass opacities and consolidations, with or without features of organizing pneumonia and without obvious dilatation of entering vessels. All dense ground glass opacities and consolidations showed abnormal perfusion with heterogeneous aspects. Pathologic findings that correspond with this CT pattern may be microvascular damage and thrombosis with ensuing infarction, intra-alveolar fibrin exudates, and hemorrhage (Fig. 1, second and third columns) .

In four of six patients, a combination of CT patterns was present ( Fig. 1, second and fourth columns) , corresponding with pathologic findings showing coexistence of patterns associated with earlier and later disease stages in the same patient.

A mixed perfusion pattern was seen in dense ground glass opacities in one patient (Fig. 1, fourth column) , without dilatation of the vessel entering the ground glass opacities. Corresponding histopathologic findings are likely related to occlusion of larger arterial structures due to in situ thrombus formation related to (possibly virus-induced) vascular damage with endotheliitis or thromboembolic occlusion (Fig. 1, fourth column) .

A combination of ground glass opacities with increased perfusion and consolidations with decreased perfusion was displayed in the same patient (data not shown), a finding also observed in histopathology and illustrating temporal heterogeneity.

Pulmonary CTA displayed (sub)segmental pulmonary embolisms, with thromboembolic aspect in two patients, with a prolonged disease course (25 and 28 d, respectively) and elevated d-dimer (7.17 and 20.54 mg/L). In CTP, no pulmonary lesion was located in the region distal to the emboli.

In this case series, we demonstrate a diverse pattern of perfusion changes in typical pulmonary lesions on CTP of patients with COVID-19 pneumonia. First, hyperperfusion through a dilated capillary system in ground glass opacities of low-to-moderate density was displayed. This is commonly observed in early inflammatory response in viral infections and also described in COVID-19 histopathology. Enlarged vessels entering ground glass opacities early in the disease course is a common finding in COVID-19 (5-7), suggested to occur due to hyperemia instead of pulmonary thrombosis, as no filling defects on corresponding CTA were observed. This double hyperperfusion pattern might explain some of the hypoxia encountered by COVID-19 patients: instead of preventing perfusion of the lung in poorly ventilated areas, we see increased flow, resulting in shunting of poorly oxygenated blood. Interestingly, the reported hyperperfusion in ground glass opacities supports the hypothesized role of the angiotensin-converting enzyme-2-regulated kallikrein-bradykinin system in COVID-19 pneumonia pathophysology (10) . Increased activation of bradykinin receptors induces a.o. vasodilation, which is precisely our observation in CTP: a double hyperperfusion pattern in ground glass opacities.

Second, in a prolonged disease course, ground glass opacities become denser with hypoperfusion on corresponding CTP, suggesting obstruction or occlusion of small arteries. This may correspond to microvascular thrombus formation and intra-alveolar extravasation, as seen in areas with fibrinous exudates and acute fibrinous organizing pneumonia and described in COVID-19 pneumonia (9) . A combination of ground glass opacities with increased perfusion and consolidations with decreased perfusion was also displayed in the same patient, which illustrates the heterogeneity of the disease, with varying involvement of pulmonary and bronchial arterial systems.

This study also supports the notion of a diseased pulmonary microvasculature later in the disease course, as on CT, areas with more consolidations and reduced perfusion are then seen, and in histopathology, microthrombi are observed (4). The temporal heterogeneity in the (density-and) perfusion patterns in this phase may reflect the complex nature of COVID-19-related coagulopathy, not previously seen in viral pneumonias (2) . However, despite intensive (mono)anticoagulation therapy, incidence of pulmonary vascular complications in COVID-19 is high. Therefore, the development of therapeutic strategies interfering early in the inflammatory phase of the disease, as to possibly prevent a disturbed interplay between the inflammatory and hemostatic environment, may constitute an attractive potential avenue of treatment. In turn, the vascular dilation and subsequent leakage induced by activation of bradykinin receptors and local inflammation may also activate the intrinsic coagulation cascade and local fibrin production, causing microvascular obstruction. Therefore, the bradykinin receptor might be an interesting target to be explored. More study of the underlying mechanisms of formation and composition of microvascular obstructive components in this distinct COVID-19 patient group is required. This study has several limitations. First, CTP is not a validated technique for assessment of perfusion in pneumonia, although CTP is described in pulmonary nodules and malignancies and is commonly used in brain imaging (8) . Second, pulmonary emboli may hinder interpretation of lung perfusion of specific lesions in this case series; however, in four patients, no pulmonary emboli were detected. In two patients, pulmonary emboli were detected outside the perfusion slab. As a third limitation, this pilot included only six patients. However, we were able to suggest perfusion patterns of the typical pulmonary COVID-19 CT features. Fourth, histology was obtained from a separate cohort. Nevertheless, we did find vascular patterns in CTP that could be matched to known pathologic findings in COVID-19. Finally, as the perfusion series is performed at one moment in time, true temporal development of changes in perfusion of the pulmonary lesions is not displayed.

The presented findings in CTP indicate biphasic pulmonary vascular dilation and obstruction and a broad spectrum of involvement at the microvascular level, corresponding with known histopathologic findings in COVID-19 pneumonia. More detailed assessment of vascular and perfusion changes is needed to increase understanding of the vascular involvement in COVID-19 disease and to develop tailored therapeutic strategies for different disease phases.

Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis

Axial CT images (A and D) and corresponding pulmonary CT angiography (CTA) images (B, C, E, F) of patient A in Figure 1 at day 4 of disease displaying dilated vessels entering ground glass opacities without filling defects on pulmonary CTA

Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: Report of the National Institute for the Public Health of the Netherlands

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

Standardized Reporting Working Group of the Dutch Radiological Society: CO-RADS -A categorical CT assessment scheme for patients with suspected COVID-19: Definition and evaluation

Initial CT findings and temporal changes in patients with the novel coronavirus pneumonia (2019-nCoV): A study of 63 patients in Wuhan, China

Hypoxaemia related to COVID-19: Vascular and perfusion abnormalities on dual-energy CT

CT perfusion in patients with lung cancer: Squamous cell carcinoma and adenocarcinoma show a different blood flow

A systematic review of pathological findings in COVID-19: A pathophysiological timeline and possible mechanisms of disease progression

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome

This work was performed at Haaglanden Medisch Centrum, The Hague, The Netherlands, and at Erasmus MC, Rotterdam, The Netherlands.Drs. von der Thüsen, Ghariq, Drijkoningen, and Quarles van Ufford contributed to study design, data acquisition and analysis; all authors contributed to data interpretation and drafting and revision of the article and agreement of accountability.The authors have disclosed that they do not have any potential conflicts of interest.For information regarding this article, E-mail: j.vonderthusen@erasmusmc.ml