Pulmonary Vascular Thrombosis in COVID-19 Pneumonia

Published:January 12, 2021DOI:https://doi.org/10.1053/j.jvca.2021.01.011

      Objectives

      During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, dramatic endothelial cell damage with pulmonary microvascular thrombosis have been was hypothesized to occur. The aim was to assess whether pulmonary vascular thrombosis (PVT) is due to recurrent thromboembolism from peripheral deep vein thrombosis or to local inflammatory endothelial damage, with a superimposed thrombotic late complication.

      Design

      Observational study.

      Setting

      Medical and intensive care unit wards of a teaching hospital.

      Participants

      The authors report a subset of patients included in a prospective institutional study (CovidBiob study) with clinical suspicion of pulmonary vascular thromboembolism.

      Interventions

      Computed tomography pulmonary angiography and evaluation of laboratory markers and coagulation profile.

      Measurements and Main Results

      Twenty-eight of 55 (50.9%) patients showed PVT, with a median time interval from symptom onset of 17.5 days. Simultaneous multiple PVTs were identified in 22 patients, with bilateral involvement in 16, mostly affecting segmental/subsegmental pulmonary artery branches (67.8% and 96.4%). Patients with PVT had significantly higher ground glass opacity areas (31.7% [22.9-41] v 17.8% [10.8-22.1], p < 0.001) compared with those without PVT. Remarkably, in all 28 patients, ground glass opacities areas and PVT had an almost perfect spatial overlap. D-dimer level at hospital admission was predictive of PVT.

      Conclusions

      The findings identified a specific radiologic pattern of coronavirus disease 2019 (COVID-19) pneumonia with a unique spatial distribution of PVT overlapping areas of ground-glass opacities. These findings supported the hypothesis of a pathogenetic relationship between COVID-19 lung inflammation and PVT and challenged the previous definition of pulmonary embolism associated with COVID-19 pneumonia.

      Graphical abstract

      Key Words

      CLINICAL MANIFESTATIONS of coronavirus disease 2019 (COVID-19) include a variety of phenotypes, spanning from asymptomatic disease to severe interstitial pneumonia with acute respiratory distress syndrome (ARDS) and death. The clinical evolution of COVID-19 can be described in three major patterns
      • Guan WJ
      • Ni ZY
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      : mild illness with upper respiratory tract clinical symptoms; non-life-threatening pneumonia; and severe pneumonia with ARDS, which begins with mild symptoms for seven-to-eight days and then rapidly progresses to symptoms requiring advanced life support.
      In addition to a possible direct cytopathic effect, the virus may elicit a local cytokine-dependent inflammatory and potentially detrimental immune reaction. The authors previously hypothesized that this host immune response may cause massive vascular endothelial and alveolar epithelial cell damage, with microvascular thrombosis leading to worsening of ventilation/perfusion imbalances and loss of hypoxic vasoconstrictor reflexes.
      • Ciceri F
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      Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): An atypical acute respiratory distress syndrome working hypothesis.
      Progression of this endothelial thrombo-inflammatory syndrome to the microvascular bed of other vital organs may result in multiple organ failure and, eventually, death. Direct viral infection of the endothelial cells, with diffuse endothelial inflammation, and apoptosis has been reported in kidney, small bowel, and lung tissue specimens from patients with COVID-19.
      • Varga Z
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      Endothelial cell infection and endotheliitis in COVID-19.
      On the other hand, pulmonary embolism has been described as part of the clinical manifestation associated with COVID-19 pneumonia,
      • Klok FA
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      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
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      Coronavirus 2019 disease (COVID-19), systemic inflammation, and cardiovascular disease.
      as have elevated D-dimers.
      • Inciardi RM
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      • et al.
      Coronavirus 2019 disease (COVID-19), systemic inflammation, and cardiovascular disease.
      • Cerdà P
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      Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis.
      • Colling ME
      • Kanti Y.
      COVID-19-associated coagulopathy: An exploration of mechanisms.
      In this peculiar pathogenic scenario, it could be argued whether pulmonary vascular thrombosis is due to recurrent thromboembolism from peripheral deep vein thrombosis (DVT) or rather to local inflammatory endothelial damage with a superimposed thrombotic late complication.
      A possible hint to such a pathogenic dilemma could come from imaging. Computed tomography (CT) pulmonary angiography is a noninvasive imaging tool able to identify filling defects in pulmonary artery branches,
      • Konstantinides SV
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      • et al.
      2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
      as well as radiologic hallmarks of COVID-19 pneumonia: bilateral ground-glass opacities (GGOs), crazy paving pattern, and/or consolidations predominantly in subpleural locations in the lower lobes.
      • Pan F
      • Ye T
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      • et al.
      Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia.
      ,
      • Ai T
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      • et al.
      Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: A report of 1014 cases.
      Furthermore, chest CT (irrespective of contrast medium administration) has been used to quantify disease burden.
      • Rotzinger DC
      • Beigelman-Aubry C
      • von Garnier C
      • et al.
      Pulmonary embolism in patients with COVID-19: Time to change the paradigm of computed tomography.
      ,
      • Grodecki K
      • Lin A
      • Cadet S
      • et al.
      Quantitative burden of COVID-19 pneumonia on chest CT predicts adverse outcomes: A post-hoc analysis of a prospective international registry.
      To address the question of whether pulmonary vascular thrombosis reflects recurrent thromboembolism from peripheral DVT or rather local thrombosis secondary to inflammatory endothelial damage, along with inflammatory markers and coagulation profile, spatial distribution of pulmonary vascular thrombosis in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia was evaluated in a consecutive cohort of patients with COVID-19 with clinical suspicion of pulmonary thromboembolism. Specifically, the topographic pattern of distribution of pulmonary vascular thrombosis was investigated using CT pulmonary angiography and then correlated with pneumonia extent.

      Methods

      This series was a subset of a larger prospective study at the San Raffaele Scientific Institute, a 1,350-bed tertiary care academic hospital in Milan, Italy; the COVID-BioB study is an institutional observational study with the aim to collect and analyze biologic samples and clinical outcomes in patients with COVID-19 (COVID-BioB, ClinicalTrials.gov NCT04318366). The study was approved by the institutional review board (protocol number 34/INT/2020). All procedures were conducted in agreement with the Declaration of Helsinki (1,964 and further amendments); informed consent was collected from all patients according to the institutional review board guidelines.
      Between March 29 and April 9, 2020, patients with a positive nasopharyngeal swab result for SARS-CoV-2, who underwent CT pulmonary angiography for clinical suspicion of pulmonary vascular thrombosis, were enrolled in this study. Last follow-up date was set at July 15, 2020. Clinical suspicion of pulmonary vascular thrombosis in patients with SARS-CoV 2 was defined as ARDS nonresponsive to increasing O2 therapy.
      Exclusion criteria were defined as (1) severe respiratory and/or motion artifacts that did not allow proper evaluation of lung parenchyma and identification of eventual filling defects in pulmonary arteries branches, and (2) pneumothorax (Fig 1).

       Clinical Data Collection

      Data were entered into a dedicated electronic case report form specifically developed on site for the COVID-BioB study. Before analysis, data managers and clinicians verified data for accuracy. Details regarding treatments administered to patients other than anticoagulants previously have been reported extensively by the authors’ group.
      • Zangrillo A
      • Beretta L
      • Scandroglio AM
      • et al.
      Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy.
      Data regarding lower- and upper-limb compression ultrasonography with Doppler evaluation also were collected to evaluate possible DVT.

       CT Protocol

      CT pulmonary angiography examinations first were performed in a dedicated CT suite (GE CT Light Speed VCT CardiacPro), easily accessible via assigned elevators and paths from the emergency department, SARS-CoV-2-dedicated intensive care units (ICUs), and COVID-dedicated wards.
      • Zangrillo A
      • Beretta L
      • Silvani P
      • et al.
      Fast reshaping of intensive care unit facilities in a large metropolitan hospital in Milan, Italy: Facing the COVID-19 pandemic emergency.
      Two additional ICUs specifically dedicated to critically ill COVID-19 patients, with a total of 24 beds, were created with a dedicated novel CT scanner (Philips CT Incisive 128 pro).
      • Zangrillo A
      • Beretta L
      • Silvani P
      • et al.
      Fast reshaping of intensive care unit facilities in a large metropolitan hospital in Milan, Italy: Facing the COVID-19 pandemic emergency.
      CT pulmonary angiography protocol included an unenhanced, breath-hold axial scan of the thorax (from lung apex to the lowest hemidiaphragm), followed by an additional scan starting a few seconds after intravenous administration of nonionic iodinate contrast medium to specifically enhance pulmonary arteries and their branches; the automatic bolus tracking technique had the region of interest positioned in the right ventricle, with a trigger threshold of 100 Hounsfield units (HU). This protocol ensured evaluation of lung parenchyma and eventual filling defects in the branches of the pulmonary arteries because an enhanced scan alone would not allow proper characterization of pneumonia.
      • Rodrigues JCL
      • Hare SS
      • Edey A
      • et al.
      An update on COVID-19 for the radiologist - A British Society of Thoracic Imaging statement.

       Image Evaluation

      All CT pulmonary angiography images were reviewed independently by two radiologists experienced in thoracic imaging (R.N. and D.P., with 28 and five years of experience, respectively) both blinded to the patient symptoms and outcome; differences in assessment were resolved with consensus. Pulmonary vascular thrombosis was defined when contrast-enhanced CT demonstrated filling defects in the branches of the pulmonary arteries and classified in distribution (number and site of pulmonary lobes affected) and extent (down to subsegmental branches). Irrespective of presence or absence of pulmonary vascular thrombosis, the diameter of perilesional subsegmental vessels always was measured on unenhanced slices; a subsegmental vessel was defined as enlarged when its axial diameter exceeded 3 mm.
      • Caruso D
      • Zerunian M
      • Polici M
      • et al.
      Chest CT features of COVID-19 in Rome, Italy.
      Imaging after processing was carried out using a commercially available software (Intellispace version 8.0, Philips Medical Systems, Chronic Obstructive Pulmonary Disease tool); after automated identification of pulmonary lobes on unenhanced slices, the software differentiated diverse areas of lung parenchyma based on HU thresholds. In the setting of SARS-CoV-2 pneumonia, the following settings were used: to quantify and differentiate between normal and pathologic lung parenchyma, a -740 HU threshold was set: areas with higher-density values were considered pathologic (disease burden). To distinguish between GGO and non-GGO (crazy paving and/or consolidation) areas, the authors applied a 660-HU threshold.
      Descriptor definitions are taken from the Fleischner Society: Glossary of Terms for Thoracic Imaging
      • Hansell DM
      • Bankier AA
      • MacMahon H
      • et al.
      Fleischner Society: Glossary of terms for thoracic imaging.
      : Ground-glass opacity is defined as a hazy increased opacity of lung, with preservation of bronchial and vascular margins; consolidation as an opacity of lung that obscures bronchial and vascular margins; and crazy paving pattern as thickened interlobular septa and intralobular lines superimposed on a background of GGO, resembling irregularly shaped paving stones.
      Software outputs refer to both lungs and single pulmonary lobes as percentages of the overall lung volume. Finally, to accurately assess the precise contribution of GGO and non-GGO patterns to the overall disease burden, the authors calculated the so-called GGO ratio, defined as the percentage of pneumonia made up by GGO.

       Statistical Analysis

      Median values with respective interquartile ranges (IQR) were used to express continuous variables, while frequencies in percentages were used for categorical variables. Patient-related variables and imaging parameters of patients with and without pulmonary vascular thrombosis were compared using the chi-square or Fisher exact test for categorical variables, and the Wilcoxon rank sum or Student t test (according to the assessment of normality) for continuous variables. The ability of GGO ratio in predicting the risk of pulmonary vascular thrombosis was determined by the area under the curve of the receiver operating characteristic curve. The optimal cutoff value predicting pulmonary vascular thrombosis was determined on the highest Youden index value (sensitivity + specificity – 1). To evaluate the cutoff accuracy, sensitivity and specificity were estimated. Comparison of GGO values between patients with or without thrombosis was evaluated using a Wilcoxon/Student's t test. Univariate and multivariate analyses were used to explore potential risk factors associated with pulmonary vascular thrombosis. The final model included D-dimer level at hospital admission and treatment with anticoagulant before CT pulmonary angiography. A p value of less than 0.05 was considered statistically significant. Statistical analyses were performed with SPSS 25 (SPSS Inc./IBM, Armonk, NY) and R version 3.3.1.

      Results

       Patient Characteristics

      Sixty-seven patients underwent CT pulmonary angiography during the study period. Following exclusions due to severe respiratory and motion artifacts (n = 9) and pneumothorax (n = 3) (Fig 1), 55 patients (39 male [70.9%] with a median age of 62 years [IQR 56-71 years]) were included in this study. Overall, 28 (50.9%) patients showed findings of pulmonary vascular thrombosis at CT pulmonary angiography imaging.
      Patient characteristics are summarized in Table 1; most patients had histories of comorbidities, with hypertension being reported in 43.1%. The median time interval between COVID-19 symptom onset and CT pulmonary angiography was 17.5 days (range: 1-38). At the time of CT pulmonary angiography, 27 patients were in COVID-19–dedicated medical wards, 19 in the ICU and nine in the emergency department.
      Table 1Baseline Characteristics of the 55 Patients With COVID-19 Who Had a Computerized Tomography Pulmonary Angiography Scan Performed at the Institute
      Characteristics (%)Overall, n = 55Without Pulmonary Vascular Thrombosis (n=27)With Pulmonary Vascular Thrombosis (n=28)p Value
      P values are calculated by chi-square or Fisher exact test (categorical variables) or Mann Whitney test (continuous variables).
      Age, y (IQR)62 (56-71)62 (56-74)62 (54.5-68)0.76
      Sex, M39 (72)19 (73)20 (71)0.89
      Ethnicity
      White47 (85)20 (74)27 (96)
      Asian8 (15)7 (26)1 (4)0.02
      Onset of COVID-19 symptoms, d17.5 (10-23)19 (10-25)14 (9-22)0.17
      Body temperature °C37.6 (36.5-38.3)38 (37- 38.7)37.4 (36- 38.2)0.07
      PaO2/FIO2 ratio247 (106.7-307)252 (91-310)247 (121-307)0.96
      BMI kg/m226 (25-31)25 (24-29)28(25-34)0.14
      Presence of comorbidities27 (52.9)11 (45.8)16 (59.3)0.33
      Hypertension0.84
      No29 (56.9)14 (58.3)15 (56)
      Yes22 (43.1)10 (41.7)12 (44)
      Coronary artery disease0.69
      No44 (86.3)20 (83)24 (89)
      Yes7 (13.7)4 (17)3 (11)
      Diabetes0.58
      No40 (78)19 (79)21 (78)
      Yes11 (22)5 (21)6 (22)
      COPD0.64
      No47 (92)22 (91.7)25 (92.6)
      Yes4 (8)2 (8.3)2 (7.4)
      Chronic kidney disease0.47
      No50 (98)23 (88.2)27 (100)
      Yes1 (2)1 (11.8)0
      Cancer0.52
      No50 (98)24 (100)26 (96)
      Yes1 (2)01 (4)
      Neurodegenerative disorders0.49
      No52 (97.1)25 (97.1)27 (100)
      Yes1 (2.9)1 (2.9)0
      WBC, × 109/L9.0 (6.3-12.3)9.2 (6.0-12.8)8.90 (6.52-12.15)0.78
      Missing000
      Lymphocyte count, × 109/L0.8 (0.7-1.2)0.9 (0.7-1.2)0.8 (0.7-1.2)0.83
      Missing321
      Neutrophil count, × 109/L7.5 (4.9-10.0)7.90 (4.65-10.65)6.8 (4.9-9.9)0.57
      Missing321
      Hemoglobin, g/dL13.5 (12.3-14.6)13 (11.5-14.2)13.6 (13.0-14.8)0.08
      Missing000
      Platelet count, × 109/L247 (194-372)248 (214-430)247 (170-328)0.27
      Missing633
      Albumin, g/L25.4 (23.6-28.2)26.0 (22.6-28.2)25.3 (23.7-28.3)0.9
      Missing1147
      ALT, U/L50 (31-73)49 (27-67)50 (32-83)0.66
      Missing633
      AST, U/L58 (45-78)59 (47-79)57 (36-87)0.52
      Missing743
      Creatinine, mg/dL10 (0.84-1.19)0.99 (0.88-1.09)11 (0.81-1.20)0.57
      Missing000
      Glucose, mg/dL109 (97-151)117 (92-154)106 (99-146)0.54
      Missing312
      Lactate dehydrogenase, U/L490 (354-540)471 (387-599)530 (342-666)0.91
      Missing110
      C-reactive protein, mg/L144 (78-218)152 (80-218)121.3 (58.2-238.2)0.78
      Missing000
      Lactate, mmol/L1.52 (1.22-1.91)1.46 (1.13-1.72)1.53 (1.25-2.15)0.30
      Missing330
      Prothrombin time1.14 (1.05-1.23)1.11 (1.05-1.20)1.18 (1.06-1.25)0.44
      Missing211
      PTT0.97 (0.89-1.04)0.97 (0.93-1.07)0.97 (0.89-1.02)0.46
      Missing211
      D-dimer, µg/mL3.00 (1.18-18.98)1.62 (0.93-6.06)10.06 (1.78-21.00)0.009
      Missing743
      Fibrinogen, mg/dL623 (503-760)686 (527-773)594 (451-701)0.18
      Missing241311
      IL6, pg/mL74 (38-134)41.8 (34.8-71.8)93.6 (48.1-216)0.02
      Missing17125
      Ferritin, ng/mL1517 (690-2869)1130 (748-2479)1990 (675-3365)0.22
      Missing963
      Creatine kinase, U/L108 (69-212)115 (75-745)85 (39-165)0.09
      Missing1165
      Procalcitonin, ng/mL0.51 (0.32-1.72)0.50 (0.34-1.07)0.95 (0.30-2.29)0.26
      Missing1468
      Pro-BNP, pg/mL287 (86-756)230 (77-747)490 (156-1121)0.28
      Missing1239
      Cardiac troponin, ng/L14.1 (7.07-28.7)12.4 (7.0-23.8)15.8 (7.6-44.6)0.53
      Missing1147
      NOTE. Results reported as median (IQR) or frequency (%).
      Abbreviations: ALT, alanine aminotransferase, AST, aspartate transaminase; BMI, body mass index; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; IQR, interquartile range; M, male; PTT, partial thromboplastin time; WBC, white blood cells.
      low asterisk P values are calculated by chi-square or Fisher exact test (categorical variables) or Mann Whitney test (continuous variables).
      At hospital admission (Table 1), the median values for white blood cell count, lymphocyte count, lactic dehydrogenase, C-reactive protein, serum ferritin, and D-dimer were 9.9 (IQR 6.3-12.3) × 109/L, 0.8 (IQR 0.7-1.2) × 109/L, 490 (IQR 354-540) U/L, 144 (IQR 78-212) mg/L, 1,517 (IQR 690-2,869) mg/L, and 3 (IQR 1.1-18) µg/mL, respectively. Baseline laboratory findings were not different between patients with or without pulmonary vascular thrombosis, except for D-dimer level (10.06 [1.78-21.00] v 1.62 [0.93-6.06]) and IL6 (93.6 [48.1-216] v 41.8 [34.8-71.8]), which were increased (p = 0.009 and p = 0.02, respectively) in patients with pulmonary vascular thrombosis.
      Laboratory findings at the time of CT pulmonary angiography are summarized in Supplemental Table 1. Before CT pulmonary angiography, 28 patients already were receiving low-molecular-weight heparin or direct thrombin inhibitor (12/28 with and 16/27 without pulmonary vascular thrombosis, p = 0.06).
      After a median follow-up of 29.5 (IQR 15-55.7) days after hospital admission, 17 patients died (eight of the patients with and nine of those without pulmonary vascular thrombosis, p = 0.7), 36 were discharged after a median time of 30 (IQR 20-56) days, and two patients were still hospitalized (one with indication of bilateral lung transplantation due to severe fibrosis). Univariate and multivariate analyses are reported in Table 2. An increased level of D-dimer at baseline (odds ratio 1.09, 95% confidence interval 1-1.18, p = 0.02) and absence of anticoagulation before occurrence of pulmonary vascular thrombosis (odds ratio 3.81, 95% confidence interval 1.21-11.9, p = 0.04) were associated independently with the increased risk of pulmonary vascular thrombosis.
      Table 2Univariate and Multivariate Logistic Regression Models on the Risk of Pulmonary Vascular Thrombosis
      CharacteristicsUnivariate, Odds Ratio (95% Confidence Interval)p ValueMultivariable, Odds Ratio (95% Confidence Interval)p Value
      Sex (female v male)0.95 (0.29-3.04)0.93
      Age (continuous)0.99 (0.95-1.04)0.91
      COVID-19 symptoms onset, d (continuous)0.94 (0.88-1.01)0.10
      Ethnicity (Asian v white)0.10 (0.02-0.93)0.04
      Hypertension (yes v no)1.12 (0.36-3.40)0.84
      Absence of anticoagulant prophylaxis before lung thrombosis (yes v no)3.81 (1.21-11.9)0.023.85 (1.01-13.9)0.04
      PO2/FIO2 (continuous)0.99 (0.95-1.00)0.73
      Neutro/lympho ratio (continuous)0.97 (0.91-1.04)0.43
      Lymphocyte count, × 109/L (continuous)1.04 (0.48-2.24)0.92
      C-reactive protein, mg/L (continuous)1 (0.99-1.05)0.90
      Lactate dehydrogenase, U/L (continuous)1 (0.99-1.03)0.70
      D-dimer, μg/mL (continuous)1.09 (1.01-1.17)0.021.09 (1-1.18)0.02
      Abbreviations: COVID-19, coronavirus disease 2019.

       Imaging Findings

       Evaluation of Pulmonary Vascular Thrombosis

      Simultaneous multiple thromboses were identified in 22 patients (78.6%), with bilateral involvement in 16 of 28 patients (57.1%) (Fig 2). The right lung was the most affected, with the highest involvement in the right lower lobe (18/28, 64.3%), followed by the upper right lobe (17/28, 60.7%) and middle lobe (8/28, 28.6%). The left lung showed involvement in 17 of 28 (60.7%) patients in the lower left lobe and 13 of 28 in the upper left (46.4%).
      Fig 2
      Fig 2Axial contrast-enhanced CT scan demonstrating simultaneous multiple thrombi with bilateral involvement (A) (blue arrows) affecting subsegmental pulmonary artery branches within extensive ground-glass opacities (B).
      Filling defects typically were found in segmental (19/28, 67.8%) and subsegmental (27/28 96.4%) branches (Fig 3); lobar branches were affected in only six patients (21.4%).
      Fig 3
      Fig 3Axial contrast-enhanced CT scan demonstrating a filling defect (A) (blue arrow) in the left upper lobe overlapping the segmental distribution of ground-glass opacities (B). Notably, no filling defects are present in the left lower lobe, where consolidation is the main radiologic pattern of pneumonia.
      The presence of an enlarged subsegmental vessel was observed in 31 patients (56.4%, median diameter: 4.2 mm [3-5.7]). Patients with pulmonary vascular thrombosis demonstrated larger subsegmental vessels compared with those without thrombosis (5.25 mm [4.42-6.4] v 2.9 mm [2.55-3.2], p < 0.001).
      Lower and upper limb compression ultrasonography with Doppler evaluation was performed in 27 of 55 patients (12 with and 15 without pulmonary vascular thrombosis). Deep vein thrombosis was detected in four patients (14.8%) (three in the pulmonary vascular thrombosis group, with popliteal and tibial vein thrombosis in one and two patients, respectively).

       Pneumonia Evaluation

      CT features of SARS-CoV-2 pneumonia are summarized in Table 3. The median disease burden was 74.7% (55.4-83.6); the most affected pulmonary lobes were the lower ones (right: 84.5% [68.35-95.17], left: 88.3% [71.8-95.5]), followed by the upper lobes (right: 67.2% [36.9-85.5], left: 71.9% [35.6-83.9]) and the middle lobe (45.7 [20.6-69.5]). No significant differences were found in disease burden between patients with pulmonary embolism and patients without (73% [33.8-82.4] v 75.4% [57.2-85.9] p = 0.35). No differences were found even when considering separately right and left lung (p = 0.26 and 0.51, respectively) or single pulmonary lobes.
      Table 3Evaluation of Lung Involvement in 55 COVID-19 Patients With Suspected Pulmonary Vascular Thrombosis
      Disease Burden (%)GGO (%)GGO Ratio (%)
      Overall (n = 55)LT (n = 28)Non-LT (n = 27)p Value
      P values are calculated by chi-square or Fisher exact test (categorical variables) or Mann Whitney test (continuous variables).
      Overall (n = 55)LT (n = 28)Non-LT (n=27)p Value
      P values are calculated by chi-square or Fisher exact test (categorical variables) or Mann Whitney test (continuous variables).
      Overall (n = 55)LT (n = 28)Non-LT (n = 27)p Value
      P values are calculated by chi-square or Fisher exact test (categorical variables) or Mann Whitney test (continuous variables).
      Lungs
      Both (RL + LL)74.75 (55.45-83.57)73.00 (33.80-82.40)75.40 (57.20-85.90)0.3522.20 (11.50-36.02)31.70 (22.90-41.00)17.80 (10.80-22.10)<0.00136.88 (23.58-64.79)57.77 (42.99-71.90)27.26 (14.50-33.91)<0.001
      RL72.35 (49.62-81.97)62.20 (36.90-78.70)77.70 (53.20-83.50)0.3621.50 (13.55-30.55)30.20 (21.50-41.00)16.80 (11.60-22.00)<0.00139.37 (22.65-65.11)64.97 (41.03-72.35)27.46 (17.39-34.69)<0.001
      LL76.30 (57.67-88.82)77.20 (36.60-89.50)75.40 (60.80-88.60)0.5120.30 (11.27-31.60)29.10 (20.10-48.10)16.20 (8.40-20.70)<0.00136.08 (21.76-63.13)62.31 (46.46-72.90)24.38 (12.64-33.39)<0.001
      Lobes
      RUL67.20 (36.87-85.55)65.50 (28.30-79.00)71.50 (46.00-86.10)0.3523.65 (11.55-32.72)30.10 (15.00-47.10)20.30 (10.70-25.60)<0.00145.83 (30.77-71.62)70.75 (50.53-83.75)34.82 (13.83-44.67)<0.001
      RML45.70 (20.65-69.55)31.70 (17.30-59.80)50.40 (26.00-73.30)01916.95 (11.65-29.55)23.10 (11.80-40.80)14.20 (11.20-20.10)<0.00153.77 (32.20-80.67)80.21 (72.06-86.15)37.30 (27.15-52.54)<0.001
      RLL84.55 (68.35-95.17)84.20 (59.80-94.40)87.50 (74.80-96.30)0.4119.95 (11.72-31.87)29.00 (23.20-43.20)13.80 (8.60-17.80)<0.00129.22 (14.59-56.94)48.10 (31.56-70.47)15.41 (11.54-24.64)<0.001
      LUL71.90 (35.62-83.95)69.60 (26.70-84.40)74.80 (42.80-80.70)0.7121.15 (12.15-40.62)35.70 (16.30-50.70)15.50 (10.80-24.60)<0.00147.51 (28.77-72.06)71.88 (53.66-77.80)35.83 (15.54-47.07)<0.001
      LLL88.30 (71.80-95.47)80.70 (53.30-95.30)89.60 (77.60-96.00)0.3419.85 (9.77-31.2)31.00 (21.60-38.60)11.70 (5.00 -19.20)<0.00129.98 (12.81-49.36)43.15 (30.11-65.36)13.41 (8.33-27.99)<0.001
      NOTE. Results reported as frequency (%) and range.
      Abbreviations: COVID-19, coronavirus disease 2019; GGO, ground-glass opacities; LL, left lobe; LLL, left lower lobe; LT, lung thrombosis; LUL, left lower lobe; RL, right lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe.
      low asterisk P values are calculated by chi-square or Fisher exact test (categorical variables) or Mann Whitney test (continuous variables).
      GGOs were present in all patients (55/55, 100%), with a median GGO burden of 22.2% (11.5-36); patients with pulmonary vascular thrombosis had significantly higher GGO areas compared with those without pulmonary vascular thrombosis (31.7% [22.9-41] v 17.8% [10.8-22.1] p < 0.001). Differences also were found when considering separately right and left lung (p < 0.001 in both cases) or single pulmonary lobes. Non-GGO pattern (crazy paving and/or consolidation) was present in 49 of 55 patients (89.1%). GGO ratio analysis also highlighted significant differences between the patients with or without pulmonary vascular thrombosis (57.8% [42.9-71.9] v 27.3% [14.5-33.9], p < 0.001). Differences also were found when considering separately right and left lung (p < 0.001 in both cases) or single pulmonary lobes.
      By means of receiver operating characteristic analysis, the authors identified as best threshold for GGO ratio a percentage of 36.4, above which patients demonstrated a higher risk of pulmonary vascular thrombosis (area under the curve: 0.864; sensitivity: 88.9%; specificity: 85.2%) (Fig 4).
      Fig 4
      Fig 4The ability of GGOs (ground-glass opacities) ratio in predicting the risk of pulmonary vascular thrombosis was determined by the area under the curve (AUC) of receiver operating characteristics (ROC) curve; the authors identified as best threshold for GGO ratio a percentage of 36.4, above which patients demonstrated a high risk of pulmonary vascular thrombosis (AUC: 0.864; sensitivity: 88.9%; specificity: 85.2%).

      Discussion

      This study showed a unique pattern of distribution of pulmonary vascular thrombosis overlapping areas of active GGOs in patients with severe COVID-19 ARDS. Most patients with pulmonary vascular thrombosis showed multiple thrombi (78.6%), with frequent bilateral involvement (57.1%) in segmental and subsegmental pulmonary artery branches, in the presence of larger subsegmental vessels within GGO areas. Furthermore, the authors confirmed an association between D-dimer values and the presence of pulmonary vascular thrombosis.
      The percentage of pneumonia characterized by pure GGO (GGO ratio) was significantly higher in patients who developed pulmonary vascular thrombosis, with a cutoff, estimated with the receiver operating characteristics analysis, of 36.4%. As a consequence, the results provided the opportunity to define a specific pattern of COVID-19 pneumonia; that is, GGO predominant, significantly associated with occurrence of pulmonary vascular thrombosis (Fig 5, central image). Ground-glass opacity is believed to represent the initial, typical response to lung injury, and roughly represents the amount of active inflammation. Furthermore, the observed subsegmental vascular enlargement previously described in SARS-CoV-2 pneumonia
      • Caruso D
      • Zerunian M
      • Polici M
      • et al.
      Chest CT features of COVID-19 in Rome, Italy.
      ,
      • Xie X
      • Zhong Z
      • Zhao W
      • et al.
      Chest CT for typical coronavirus disease 2019 (COVID-19) pneumonia: Relationship to negative RT-PCR testing.
      also has been associated with SARS-CoV-2–triggered hyperemia. The results pointed out a reliable association between subsegmental vascular enlargements within a GGO prevalent pneumonia and the presence of multiple bilateral pulmonary vascular thromboses in the peripheral branches of each lobe artery.
      Fig 5
      Fig 5Central image/visual abstract: Computed tomography pulmonary angiography (CTPA) imaging demonstrating, in three different clinical scenarios, eventual filling defects in branches of the pulmonary arteries (white arrows) and their spatial distribution according to the corresponding ventilation maps (white asterisks indicate normal lung parenchyma). In (A) (non-COVID-19 pneumonia) and (C) (non-COVID-19 ARDS) filling defects are electively found in the branches of the pulmonary arteries, accountable for the vascularization of healthy lung segments. On the contrary, in (B) (COVID-19 pneumonia), there is an almost perfect topographical overlap between filling defects distribution and pneumonia extent. COVID-19, coronavirus disease 2019.
      Poissy et al.
      • Poissy J
      • Goutay J
      • Caplan M
      • et al.
      Pulmonary embolism in patients with COVID-19: Awareness of an increased prevalence.
      recently reported a 20.6% pulmonary embolism incidence among the first 107 consecutive patients with COVID-19 admitted to their ICU in France and receiving prophylactic antithrombotic treatment. Grillet et al.
      • Grillet F
      • Behr J
      • Calame P
      • et al.
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      also reported that the proportion of patients with acute pulmonary embolism was 23% in the subgroup of 100 patients with COVID-19 infection and severe clinical features (among the 280 hospitalized patients in the study period).
      Overall, the current findings confirmed the ability of CT scan to provide a quantitative assessment of the disease severity and confirm the extension of active inflammation as the major determinant of pulmonary vascular thrombosis.
      • Ye Z
      • Zhang Y
      • Wang Y
      • et al.
      Chest CT manifestations of new coronavirus disease 2019 (COVID-19): A pictorial review.
      Multiple and bilateral pulmonary thromboembolic events already have been reported in patients with COVID-19.
      • Yang R
      • Li X
      • Liu H
      • Zhen Y
      • et al.
      Chest CT severity score: An imaging tool for assessing severe COVID-19.
      However, a systematic topographic analysis of this pattern was lacking and, instead, an embolism concept was proposed; the authors showed stringent pulmonary vascular thrombosis topographic distribution in overlap with GGO areas. Overall, these features supported the concept of an atypical COVID-19-associated ARDS, because the pattern of distribution of pulmonary thromboembolic events in typical ARDS involves areas spared by inflammatory changes.
      • Chiumello D.
      Acute respiratory distress syndrome (ARDS): Definition, incidence, and outcome.
      The presence of a high percentage of lung involvement on chest CT has been shown to range between six and 13 days from symptom onset
      • Pan F
      • Ye T
      • Sun P
      • et al.
      Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia.
      ,
      • Hong SB
      • Kim HJ
      • Huh JW
      • et al.
      A cluster of lung injury associated with home humidifier use: Clinical, radiological and pathological description of a new syndrome.
      ; the median time in pulmonary vascular thrombosis presentation (17.5 days) fits with the hypothesis of an intermediate stage disease,
      • Bernheim A
      • Mei X
      • Huang M
      • et al.
      Chest CT findings in coronavirus disease-19 (COVID-19): Relationship to duration of infection.
      in which lung inflammation is at its highest, resulting in possible progressive endothelial damage. Subsequent activation of the coagulation cascade in the microvascular compartment could lead to a critical functional deterioration of O2 exchange, ultimately unresponsive to mechanical ventilation.
      There is increasing evidence supporting the important role of endothelial cells in the initiation of inflammation and in the development of extensive pulmonary intravascular coagulopathy, which is common in COVID-19 patients with ARDS.
      • McGonagle D
      • O'Donnell JS
      • Sharif K
      • et al.
      Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.
      • Teuwen LA
      • Geldhof V
      • Pasut A
      • et al.
      COVID-19. The vasculature unleashed.
      • Cao W
      • Li T.
      COVID-19. Towards understanding of pathogenesis.
      However, it long has been known that not only diffuse alveolar damage but also pulmonary vascular injury are central pathologic features of ARDS.
      • Blaisdell FW.
      Pathophysiology of the respiratory distress syndrome.
      ,
      • Tomashefski Jr JF
      • Davies P
      • Boggis C
      • et al.
      The pulmonary vascular lesions of the adult respiratory distress syndrome.
      Disregulated inflammation and endothelial cell direct injury promote the expression of coagulation-initiating factors, like tissue factor on cell surfaces, thereby causing downstream activation of coagulation. At the same time, natural anticoagulant mechanisms, including antithrombin, tissue factor pathway inhibitor, and the protein C system, are suppressed and this further propagates an uncontrolled cycle of coagulation.
      • Opal SM.
      Interactions between coagulation and inflammation.
      ,
      • Levi M
      • van der Poll T.
      The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients.
      Other authors suggest that the disruption of pulmonary circulation causes platelet and fibrinogen depletion, suggesting local thrombosis formation.
      • Fraser DD
      • Patterson EK
      • Slessarev M
      • et al.
      Endothelial injury and glycocalyx degradation in critically ill coronavirus disease 2019 patients: Implications for microvascular platelet aggregation.
      Histologic postmortem studies revealed diffuse extensive fibrin thrombosis of small and large pulmonary arteries and lung necrosis distal to vascular obstruction in ARDS of diverse etiology.
      • Greene R
      • Zapol WM
      • Snider MT
      • et al.
      Early bedside detection of pulmonary vascular occlusion during acute respiratory failure.
      • Zapol WM
      • Kobayashi K
      • Snider MT
      • et al.
      Vascular obstruction causes pulmonary hypertension in severe acute respiratory failure.
      • Hill JD
      • Ratliff JL
      • Fallat RJ
      • et al.
      Prognostic factors in the treatment of acute respiratory insufficiency with long-term extracorporeal oxygenation.
      Furthermore, bedside balloon occlusion pulmonary angiography demonstrated pulmonary artery filling defects of diverse severity and etiology in about one-half of the patients with ARDS.
      • Greene R
      • Zapol WM
      • Snider MT
      • et al.
      Early bedside detection of pulmonary vascular occlusion during acute respiratory failure.
      Severity of the respiratory insufficiency, pulmonary artery pressure, pulmonary vascular resistance, and mortality were significantly higher in patients with angiographic evidence of vascular obstruction than in those with normal angiography.
      • Greene R
      • Zapol WM
      • Snider MT
      • et al.
      Early bedside detection of pulmonary vascular occlusion during acute respiratory failure.
      Other authors used the same angiographic technique and found multiple pulmonary artery filling defects in a relevant fraction of patients with severe ARDS.
      • Vesconi S
      • Rossi GP
      • Pesenti A
      • et al.
      Pulmonary microthrombosis in severe adult respiratory distress syndrome.
      Overall, even if understanding the role of pulmonary vascular thrombosis in the development of pulmonary hypertension in the course of ARDS is of paramount importance, there still is uncertainty. Besides functional mechanisms, there is evidence of reduced small pulmonary artery diameter by medial artery thickening, and significant reduction in total artery concentration even after short-course ARDS.
      • Snow RL
      • Davies P
      • Pontoppidan H
      • et al.
      Pulmonary vascular remodeling in adult respiratory distress syndrome.
      Because ARDS is a syndrome caused by some primary clinical condition (pneumonia, trauma, shock, sepsis, multiple transfusions, etc.), that could initiate intravascular coagulation; it is not always clear what the main reason is for the observed pulmonary vascular thrombosis in ARDS. The abovementioned studies found a significantly higher rate of thrombotic vascular occlusion in posttraumatic ARDS and in patients with signs of concomitant disseminated intravascular coagulation syndrome.
      • Greene R
      • Zapol WM
      • Snider MT
      • et al.
      Early bedside detection of pulmonary vascular occlusion during acute respiratory failure.
      ,
      • Vesconi S
      • Rossi GP
      • Pesenti A
      • et al.
      Pulmonary microthrombosis in severe adult respiratory distress syndrome.
      Despite extensive research from the 1970s, the understanding of the basic mechanisms of lung injury and of pulmonary vascular thrombosis in non-COVID-19 ARDS still is uncertain.
      As a limitation, the authors acknowledge that this study reported a subset cohort of a larger institutional prospective study. Furthermore, the clinical progression of respiratory distress in this cohort was associated with, but not necessarily caused by, the increased level of D-dimers. On top of this, all consecutive patients undergoing a CT scan for clinical suspicion of pulmonary vascular thrombosis were enrolled; therefore, the overall prevalence in those not presenting clinical suspicion remains unknown. Importantly, in the authors’ hospital, deep vein thrombosis
      • Baccellieri D
      • Bertoglio L
      • Apruzzi L
      • et al.
      Incidence of deep venous thrombosis in COVID-19 hospitalized patients during the first peak of the Italian outbreak.
      was found only in a relatively small percentage of patients with lung thrombosis, and there were no cases in the iliofemoral venous axis, supporting the hypothesis of a lung disease–related complication, due to SARS-CoV2 pathogenicity. The limitation linked to data collected from a single center remains, yet the critical role of the association of disorders in the coagulation pathway, disease severity, and death have been reported in independent cohorts in patients with COVID-19.
      • Klok FA
      • Kruip MJHA
      • Van der Meer NJM
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ,
      • Kashi M
      • Jacquin A
      • Dakhil B
      • et al.
      Severe arterial thrombosis associated with Covid-19 infection.
      ,
      • Inciardi RM
      • Solomon SD
      • Ridker PM
      • et al.
      Coronavirus 2019 disease (COVID-19), systemic inflammation, and cardiovascular disease.
      ,
      • Al-Samkari H
      • Karp Leaf RS
      • Dzik WH
      • Carlson JCT
      • et al.
      COVID-19 and coagulation: Bleeding and thrombotic manifestations of SARS-CoV2 infection.
      Acute systemic inflammation features previously have been associated with disease severity and mortality.
      • Colling ME
      • Kanti Y.
      COVID-19-associated coagulopathy: An exploration of mechanisms.
      ,
      • Ciceri F
      • Castagna A
      • Rovere-Querini P
      • et al.
      Early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy.
      Importantly, D-dimer levels should be considered as an additional predictive tool to stratify patients at risk of adverse outcome and may guide physicians to proceed with CT pulmonary angiography as well as assign anticoagulant administration.
      Prospective ongoing randomized trials currently are evaluating the intensity of prophylactic anticoagulation (FREEDOM COVID-19,

      FREEDOM COVID-19 anticoagulation strategy (FREEDOM COVID). ClinicalTrials.gov identifier: NCT04512079. Available at: https://clinicaltrials.gov/ct2/show/NCT04512079. Accessed December 30, 2020.

      INHIXACOV19

      Enoxaparin in COVID-19 moderate to severe hospitalized patients (INHIXACOV19). ClinicalTrials.gov identifier: NCT04427098, Available at: https://clinicaltrials.gov/ct2/show/NCT04427098. Accessed December 30, 2020.

      ), as well as the use of targeted drugs on endothelium (DEFACOVID,

      Defibrotide as prevention and treatment of respiratory distress and cytokine release syndrome of Covid 19 (DEFACOVID). ClinicalTrials.gov identifier: NCT04348383, Available at: https://clinicaltrials.gov/ct2/show/NCT04348383. Accessed December 30, 2020.

      DEFI-VID19

      Defibrotide in COVID-19 pneumonia (DEFI-VID19), ClinicalTrials.gov identifier: NCT04335201 Available at: https://clinicaltrials.gov/ct2/show/NCT04335201. Accessed December 30, 2020.

      ). Treatment of COVID-19 pneumonia is changing rapidly with the availability of the results of clinical trials. Immunomodulation therapies to reduce the risk of cytokine- release syndrome induced by SARS-CoV-2 has demonstrated efficacy in single-center and multicenter trials.
      • Cavalli G
      • De Luca G
      • Campochiaro C
      • et al.
      Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: A retrospective cohort study.
      ,
      • Sanders M
      • Monogue ML
      • Jodlowski TZ
      • et al.
      Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review.
      In conclusion, this study supported the hypothesis of a pathologic relationship between lung inflammation and pulmonary vascular thrombosis, definitively challenging the previous definition of embolism associated with COVID-19 pneumonia and strongly supporting the rationale for an association of anti-inflammatory and anticoagulant treatments in patients with severe COVID-19 pneumonia.

      Acknowledgments

      The authors are indebted to all healthcare personnel who helped during the COVID-19 emergency.

      Conflict of Interest

      None.

      Appendix. Supplementary materials

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