key: cord-0807484-gg6qfx1w authors: Cavagna, Enrico; Muratore, Francesco; Ferrari, Fabio title: Pulmonary Thromboembolism in COVID-19: Venous Thromboembolism or Arterial Thrombosis? date: 2020-07-09 journal: Radiol Cardiothorac Imaging DOI: 10.1148/ryct.2020200289 sha: b2a08a31f2cdc08ad57ea293158fe664e76fa097 doc_id: 807484 cord_uid: gg6qfx1w BACKGROUND: Coronavirus disease 2019 (COVID-19) in hospitalized patients is frequently complicated by pulmonary thromboembolism (PTE). PURPOSE: To investigate CT pulmonary angiography (CTPA) findings of PTE in COVID-19 and its association with clinical and radiological conditions. MATERIALS AND METHODS: This retrospective study includes 109 hospitalized patients with COVID-19 who underwent CTPA for suspected PTE from March 20 to May 3, 2020. Data were collected from our PACS. CTPA findings of PTE were evaluated. Based on the presence or absence of PTE, patients were divided in two groups and the clinical and radiological conditions were compared using Mann-Whitney U test and χ(2) test. RESULTS: Study population comprised 82M/19F, mean age 64.1±15.0 [95% confidence interval CI:60.4-67.6] years. CTPAs were performed 19.8±6.1 [95% CI:18.1-20.2] days after the symptom onset and 10.5±3.8 [95% CI:10.2-12.9] days after the admission. Patients with PTE were 41/101(40.6%). PTE was mostly bilateral or only right (37/41[90.2%]), mainly involved segmental (37/41[90.2%]) or subsegmental (25/41[61.0%]) arteries, and affected mainly the lower lobes branches (30/41[73.2%]). Parenchymal segments supplied by segmental arteries with PTE showed a prevalent consolidation pattern (25/37[67.6%]). Deep vein thrombosis (DVT) was present only in 5/41(12.2%). Comparing groups with and without PTE, no significant difference was observed in age, gender, onset symptoms, comorbidities, tumor history, use of respiratory supports, activated partial thromboplastin time, prothrombin time and DVT. Conversely, differences were evaluated in CT lesion score (15.7±1.4 [95% CI:15.3-16.1] vs 14.1±1.1 [95% CI:13.8-14.4], p=0.035); d-dimer (p<0.001); lactate dehydrogenase (LDH) (p<0.001), and C-reactive protein (CRP) (p=0.042). CONCLUSION: PTE in COVID-19 involves mainly the segmental and sub-segmental arteries of segments affected by consolidations in patients with more severe lung disease. We hypothesize that the development of PTE in COVID-19 might be a pulmonary artery thrombosis due to severe lung inflammation and hypercoagulability rather than thromboembolism. I n p r e s s pneumonia, can stimulate thrombosis not only through increasing blood viscosity, but also via a hypoxia-inducible transcription factor-dependent signaling pathway [8] . For these reasons, anticoagulation therapy in severe COVID-19 patients has been recommend [9, 10] . Despite systematic thromboprophylaxis, Klok et al. [11] reported an incidence of 31% for thrombotic complications in intensive care unit patients with COVID -19. Few studies and isolated clinical cases of COVID-19 pneumonia with pulmonary thromboembolism (PTE) have been recently published [12 -16] . Poissy et al. [15] postulated an increased prevalence of PTE in COVID-19 patients and Danzi et al. [16] suggested that severe COVID-19 pneumonia could be a precipitant factor for acute PTE in the absence of major predisposing factors. The awareness of such complication is essential because it could cause clinical deterioration [17] . Therefore, the aim of this study is to investigate computed tomography pulmonary angiography (CTPA) findings of PTE in patients with COVID-19 and its association with clinical and radiological conditions. All procedures performed on studies involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Our study protocol was approved by the Institutional Review Board of our Hospital; written informed consent was waived. No industry support was given. This retrospective study includes 109 hospitalized patients with COVID-19 confirmed by RT-PCR on oropharyngeal swab, who underwent CTPA for suspected PTE from March 20 to May 03, 2020. Data were collected from the PACS of "Infermi" Hospital Rimini, a tertiary center in Northern Italy. All CTPAs were performed due to the sudden onset of clinical deterioration with unexplained worsening of dyspnea, symptoms suggestive for PTE, d-dimer elevation, or in case of mismatch I n p r e s s between clinical worsening and chest radiograph stability. Eight patients with non-diagnostic CTPA were excluded: 5 because of motion artifacts and 3 due to attenuation values in the mean pulmonary artery (MPA) lower than 250 HU; this threshold is considered optimal for PTE evaluation [18, 19] . Our final cohort was composed by 101 patients. CT acquisition protocol and post-processing CT examinations were performed using a 64-row multi-detector CT scanner (Lightspeed VCT, GE Healthcare U.S.); patients laid in supine position with arms elevated. A 20-gauge cannula was inserted into a superficial vein of the right antecubital fossa, connected to a two-way power injector. All patients were examined with the same standardized protocol, based on two acquisitions from the lung apices to the costophrenic recess; first a non-contrast-enhanced scan, then a contrast-enhanced scan. The scan parameters were tube voltage 120 kVp with automatic tube current modulation, pitch = 0.95, matrix = 512×512 pixels, and field of view = 350 mm×350 mm. A volume of 70 ml of contrast medium (Iomeprol, 400 mgI/ml; Bracco Imaging, Milan, Italy) was injected at a flow rate of 4 ml/s with a bolus tracking technique, followed by 40 ml of saline solution at the same rate. A circular region of interest (ROI) was placed within the MPA; the acquisition started automatically when a threshold of 100 HU (Hounsfield Units) was reached. All images were reconstructed with a slice thickness of 0.625-1.250 mm with the same increment, using an iterative reconstruction algorithm. The lung parenchyma was evaluated using a sharp filter with window/level of 1200/-600 HU and mediastinal structures were evaluated using a softer filter with window/level of 350/50 HU. Multi-planar reconstruction and maximal intensity projection were also generated. Two radiologists in consensus (one with more than 5 years, and the second with more than 20 years of experience in chest imaging) retrospectively evaluated the CT examinations. A semi-quantitative scoring system was used to quantitatively estimate the pulmonary involvement of all these abnormalities based on the area involved. Each lobe was visually scored from 0 to 5 as: 0, no involvement; 1, <5% involvement; 2, 25% involvement; 3, 26%-49% involvement; 4, 50%-75% involvement; 5, >75% involvement. The total CT score was the sum of the individual lobar scores and ranged from 0 (no involvement) to 25 (maximum involvement) [20] . The following diagnostic criteria for PTE were used: intraluminal filling defects or non-visualization of the pulmonary arteries compared to the contralateral side. The obstruction CT index was calculated as described by Qanadli et al. [21] . Pulmonary artery diameter and right ventricle dilatation were evaluated. For each patient age, sex, onset symptoms (fever, cough, dyspnea, myalgia or fatigue, diarrhea, nausea and vomiting), number of comorbidities, smoking history, and oncologic history were collected. Moreover, for each patient, the following laboratory tests were collected within 48 hours after the CT examinations: activated partial thromboplastin time (aPTT), prothrombin time (PT), lactate dehydrogenase (LDH), C-reactive protein (CRP), d-dimer. The use of mechanical respiratory support, presence of deep venous thrombosis (DVT) and the type of therapy were annotated. Finally, the CT score of the pulmonary lesions at non-contrast acquisition was collected. Venous duplex-ultrasound of the lower extremities was performed routinely in all patients. A dedicated statistical software was used (MedCalc v19.1.6, MedCalc Software, Ostend, Belgium). Continuous variables were displayed as mean ± standard deviation and categorical variables were reported as counts and percentages. CTPA findings suggestive of PTE were evaluated. Based on the presence or absence of PTE, patients were subdivided in two groups. Group 1, with PTE, and Group I n p r e s s smoking history, oncologic history, use of ventilatory support, aPTT, PT, LDH, CRP, d-dimer, presence of DVT, and CT score were compared between two groups, using Mann-Whitney U test and χ2 test, respectively, for continuous and categorical variables. This was a convenience sample; therefore, no statistical power analysis was done a priori for comparing the distribution of variables between Groups 1 and 2. A p-value <0.05 was defined as statistically significant. Comparing groups with and without PTE, no statistically significant difference was observed in age, sex, presentation symptoms such as fever, cough and dyspnea, number of comorbidities, smoking or oncologic histories, use of ventilatory support, aPTT, PT, or presence of DVT. Conversely, differences were noted in the CT score ( Table 3 . Blood hypercoagulability is a common finding among hospitalized patients with COVID-19 [5] . The effect of COVID-19 on pulmonary coagulation and the resulting development of PTE could be due to proinflammatory cytokines, endothelial dysfunction and hypoxia [6, 8] . Several papers report high incidence of PTE in COVID-19, ranging from 22% to 39% [10, 11, 12, 13, 14, 15, 17, 22] : the awareness of such complication is of vital importance, because it can lead severe clinical deterioration. We carried out a retrospective study to investigate CTPA findings of PTE in hospitalized patients with COVID-19 and its association with radiological and clinical parameters. In our study, thromboembolism was confirmed in a high percentage of patients (40.6%). The overall prevalence of PTE in our series is higher relative to that previously reported in the literature (22% -39%) [10, 11, 12, 13, 14, 15, 17, 22] . A possible explanation of this high frequency is that we collected patients from the beginning of the pandemic, who did not undergo appropriate prophylaxis. Our findings differ from the study of Grillet et al. [12] who reported lower PTE incidence (23%) in patients with severe COVID-19. The two studies differ in some aspects; in the latter, information about d-dimer was not collected and association between CT severity score and PTE was not attempted. Our study confirmed that more severe COVID-19 pneumonia, as scored by CT, and increased laboratorial biomarkers (d-dimer, LDH and CRP) were more commonly associated with PTE. However, Grillet et al. [12] did report an association between invasive mechanical ventilation and male gender with PTE, which was not evident in our cohort. We hypothesized that PTE is a common complication of severe COVID-19 pneumonia occurring a few weeks after symptoms onset. In support of our hypothesis, we carried out a literature review about PTE in previous similar pandemics caused by SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). SARS-CoV infection has been responsible for various coagulation abnormalities and multiple vascular thromboses commonly seen in lungs, suggesting that an underlying thrombophilic state can induce pulmonary artery thrombi formation [23] . In the same way, hematological manifestations of MERS include thrombocytopenia and coagulopathy with an associated status of disseminated intravascular coagulation at different sites, including the pulmonary arteries [24] . In the present study, PTE was mostly bilateral (48.7%) or only involving the right lung (41.5%); it often involved the small caliber peripheral pulmonary arteries, such as segmental (90.2%) or subsegmental (61.0%) branches, as already described by Chen et al [22] , especially in the lower lung lobes. Because of the small caliber of the vessels involved, the main PTE finding was vascular I n p r e s s cut-off. Indeed, it is of interest to note that parenchymal segments supplied by segmental arteries with PTE often showed prevalence of CT consolidation pattern 25/37 (67.6%). Besides, the number of exclusively segmental arteries (34.1%) or only subsegmental arteries involved (19.5%) is higher than those reported in non-COVID-19 series [25, 26] . These sites seem to correspond to the most common distribution of COVID-19 opacities [27] . Using a parallel rationale, Zotzmann et al. [28] suggested that subpleural consolidations in COVID-19 should prompt further diagnostic workup due to the potential occurrence of PTE. In our study lower extremity venous Duplex Ultrasound (DUS) was performed in all hospitalized patients; interestingly, DVT was rarely concomitant with PTE (12.2%). When comparing groups with and without PTE, no differences were noted in the presence of DVT (p=0.9820). However, we cannot exclude that thrombi arising from different body regions could have contributed to the PTE observed in our series, since DUS would miss thrombi residing in the abdominopelvic or upper limbs. Besides, we cannot exclude that patients who had DVT with no PTE could have developed PTE later on, since a hypercoagulable state is also present in these patients. Moreover, between the two groups with and without PTE, no difference was observed according symptoms at presentation of COVID-19, number of comorbidities, oncologic history or use of respiratory support. Thus, we hypothesize that the development of PTE in severe COVID-19 pneumonia could be related to severe lung inflammation rather than to common risks factors for PTE or DVT. Considering potential limitations related to the narrow statistical power of our small sample, these preliminary findings -as also stated by previous authors [15] -may support the hypothesis that filling defects seen in pulmonary artery branches could be related to thrombosis Our study has some limitations. First, it was retrospective and monocentric, leading to increased risk for selection bias. Second, the influence of the therapies was not evaluated. Third, study design and relatively small sample size of patients with PTE have limited power to definitively address the thrombosis versus embolism conundrum. PTE is frequently observed in COVID-19 patients and mainly involves the segmental and subsegmental arteries supplying the lung parenchyma affected by consolidation. Patients with more severe COVID-19 pneumonia, as scored by CT, and with increased laboratorial biomarkers (ddimer, LDH and CRP) were more commonly affected by PTE. These findings are in keeping with other observations showing that COVID-19 triggers a hypercoagulable state, and also contribute to the discussion between pulmonary artery thrombosis versus venous thromboembolism as potential hypotheses for this phenomenon. The authors declare no potential conflict of interest associated with this study. All procedures performed on studies involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was waived due to the COVID-19 emergency situation. This research did not receive any specific grant from funding agencies in the public, commercial or not for profit sectors. 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