key: cord-0730911-csubu1d3
authors: Müller-Peltzer, Katharina; Krauß, Tobias; Benndorf, Matthias; Lang, Corinna N.; Bamberg, Fabian; Bode, Christoph; Duerschmied, Daniel; Staudacher, Dawid L.; Zotzmann, Viviane
title: Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS
date: 2020-09-11
journal: Respir Med
DOI: 10.1016/j.rmed.2020.106135
sha: 5ff3a2e5bf2a79b6333e417247dbd582e5179817
doc_id: 730911
cord_uid: csubu1d3

PURPOSE: Patients hospitalized for infection with SARS-CoV-2 typically present with pneumonia. The respiratory failure is frequently complicated by pulmonary embolism in segmental pulmonary arteries. The distribution of pulmonary embolism in regard to lung parenchymal opacifications has not been investigated yet. METHODS: All patients with COVID-19 treated at a medical intensive care unit between March 8th and April 15th, 2020 undergoing computed tomography pulmonary angiography (CTPA) were included. All CTPA were assessed by two radiologists independently in respect to parenchymal changes and pulmonary embolism on a lung segment basis. RESULTS: Out of 22 patients with severe COVID-19 treated within the observed time period, 16 (age 60.4 ± 10.2 years, 6 female SAPS2 score 49.2 ± 13.9) underwent CT. A total of 288 lung segment were analyzed. Thrombi were detectable in 9/16 (56.3%) patients, with 4.4 ± 2.9 segments occluded per patient and 40/288 (13.9%) segments affected in the whole cohort. Patients with thrombi had significantly worse segmental opacifications in CT (p < 0.05) and all thrombi were located in opacitated segments. There was no correlation between d-dimer level and number of occluded segmental arteries. CONCLUSIONS: Thrombi in segmental pulmonary arteries are common in COVID-19 and are located in opacitated lung segments. This might suggest local clot formation.

In hospitalized patients infected with SARS-CoV-2, respiratory failure is a common complication [1] .

Since the beginning of the outbreak, multiple studies evaluating imaging techniques described bilateral ground-glass opacities, crazy-paving and air-space consolidations in peripheral and basal distribution in patients with COVID-19 pneumonia [2, 3] . Some of these studies have investigated the changes of parenchymal opacifications during the time of infection and the assessment of severity using chest CT-scans [4] [5] [6] .

Apart from COVID-19 pneumonia, a coagulopathy is reported in a considerable number of patients [7] . Notably, elevated d-dimer levels correlate with poor prognosis in COVID-19 [8] . Several case reports and retrospective analyses report thrombotic complications, most of which are pulmonary embolisms [9] [10]. Therefore, the association between SARS-CoV-2 infection and disseminated intravascular coagulation, D-dimer levels, deep vein thrombosis, pulmonary embolisms, and microvascular thrombosis is under investigation [8, 9, 11] . Interestingly, during the initial SARS-CoV-2 outbreak in China, pulmonary embolisms were not described. One possible explanation is the fact that mostly chest CT scans without contrast medium were used [2] [3] [4] [5] [6] . The pathological mechanism causing pulmonary embolism in COVID-19 remains unclear. It has been speculated that endothelial inflammation promotes thrombosis and hypoxic pulmonary vasoconstriction might facilitate local thrombus formation mediated by activation of complement pathways and an associated procoagulant state [7] [12]. This would require pulmonary artery thrombosis to be formed locally, in areas of active SARS-CoV-2 pneumonia. To our best knowledge, the distribution of pulmonary embolism in regard to lung parenchymal opacifications and normal parenchyma has not been investigated yet. Therefore, the aim of our study was to investigate if pulmonary embolism manifestations are limited to lung segments affected by CoVID-19 pneumonia.

The hypothesis of our study, that pulmonary artery thrombi would not be present in non-COVID-19 affected lung segments, was made before starting the examination and only this endpoint was evaluated. Pulmonary angiography CT scans were performed using a commercial CT scanner (SOMATOM Definition Flash; Siemens Healthineers GmbH, Forchheim, Germany) with the following scanning parameters: tube voltage, 100 kV; tube current, 90 mAs; rotation time, 0.28 s. 128 x 0.6 mm collimation with automated dose modulation (CARE dose4D, Siemens Healthineers GmbH, Forchheim, Germany).

Images were reconstructed at 1 mm slice thickness with an increment of 0,6 mm with an advanced modeled iterative reconstruction using I26f (mediastinal) and B50f (lung) kernels (Siemens Healthineers GmbH, Forchheim, Germany).

Patients without extracorporeal membrane oxygenation (ECMO) received the standard pulmonary angiography protocol with bolus-tracking method. 70 ml contrast agent (Imeron 400, Bracco Imaging, Germany) followed by a 50 ml bolus saline solution were injected at a flow rate of 4 ml/s using a jugular central venous line. The region of interest (ROI) was placed in the pulmonary trunk. The CT scan started after a threshold of 100 Houndsfield units (HU) was reached within the ROI. To give consideration to an altered blood flow in patients with ECMO device the amount of contrast agent was adjusted to 100 ml and the ROI was placed in the air. The scan was manually started when an adequate contrast was visually detected in the pulmonary trunk. If tolerated by the patient ECMO flow was reduced to 70 to 50 % of the initial value after scout acquisition for the time of the contrast enhanced scan.

Two radiologists (KMP, TK) with 6 and 13 years of experience in thoracic radiology assessed the CTPA (computed tomography pulmonary angiography) scans in consensus reading for image quality, parenchymal changes and pulmonary embolism. All scans were viewed in axial and coronal 1 mm slices at standard lung and soft tissue window. Pulmonary artery contrast was documented using a ROI with a standardized size of 70 mm 2 , which was placed in the right and left main pulmonary artery, respectively. Average HU and standard deviation within the ROIs were documented. Overall image quality of each CTPA scan was evaluated based on imaging contrast and breathing artifacts using a five-point Likert scale (1. excellent contrast in all pulmonary vessels, no motion artifacts due to breathing; 2. good contrast in all pulmonary vessels, minimal motions artifacts due to breathing; 3. acceptable contrast in central and peripheral pulmonary vessels, sparse motions artefacts due to breathing in basal pulmonary segments; 4. Acceptable contrast in central and poor contrast in J o u r n a l P r e -p r o o f peripheral pulmonary vessels, moderate motion artifacts due to breathing in basal lung segments; 5.

Poor contrast in central and unacceptable contrast in peripheral pulmonary vessels, distinct motion artifacts due to breathing in apical and basal lung segments).

Each pulmonary lung segment was separately evaluated for parenchymal abnormalities and pulmonary embolism. Parenchymal abnormalities were grouped in non-consolidating changes, including ground-glass opacities and/or crazy-paving pattern, and air space consolidation. No patient in the collective showed centrilobular nodules or parenchymal reticulation without underlying GGO (ground-glass opacification). Segmental parenchyma was defined by the dominating pattern as nonconsolidating, consolidating, or, in case of an equal distribution of non-consolidating and consolidating changes, as mixed. Ground-glass opacification was defined as parenchyma with hazy increased attenuation without obscuration of underlying vessels. Crazy-paving was defined as ground-glass opacification with superimposed interlobular septal thickening and intralobular lines [13] . Parenchymal opacifications were delineated as air space consolidation when the opacifications obscured the underlying pulmonary vessels. A lung segment without any of the above-mentioned opacifications was defined as normal.

A segmental or subsegmental pulmonary embolism was defined as central filling defect within a vessel surrounded by contrast material when orthogonal or parallel to the long axis of the vessel as well as eccentric wall adherent filling defect rendering an acute angle with the vessel wall as well as complete occlusion of a dilated vessel [14] .

Statistical analysis was performed using dedicated software (R 3.6.1.). The unpaired two-samples

Wilcoxon test was used to analyze the association of contrast enhancement in the main pulmonary arteries and image quality. Fisher`s exact test was used for contingency table analysis. Significance level was set at p<0.05. This retrospective study was approved by the ethics committee of the Albert Ludwig University of Freiburg (file number 234-20).

A total of 18 patients with COVID-19 pneumonia underwent CTPA within 7.5 ± 12.1 days after admission to the ICU. Two patients had to be excluded from the study, 1 for not undergoing contrastenhanced CT and 1 for massive chronical emphysematous lung parenchyma destruction, which could not be evaluated for signs of atypical pneumonia. The process of patient selection is shown in figure   1 . Six female and 10 male patients were included in this analysis. The patients' age ranged between 47 and 77 years with a mean age of 62. 

We did not observe an association between d-dimer level and number of affected segments in the patients with proven PAT (Pearson correlation coefficient r=-0.05, p=0.90). There was a trend towards higher d-dimer levels in patients with PAT compared to those without not reaching statistical significance (20.03±15.33 mg/l FEU versus 9.00±6.15 mg/l, unpaired two-samples Wilcoxon test P=0.20. However, all d-dimer levels >20.00 mg/l FEU were observed in patients with at least one segment with confirmed PAT (Fisher's exact test p=0.08).

We found PAT in 9 out of 16 patients (56%) with COVID-19 undergoing contrast enhanced CTPA. This is a higher rate than previously reported, which may be biased by referral of the sickest patients to our ARDS/ECMO center. A study of 100 COVID-19 patients undergoing CTPA, pulmonary embolism was found in 25% [7] . Another study reported PAT in 18% of all patients [15] . A post mortem study of 12 autopsies however suggested PAT be the cause of death in 33% in COVID-19 [10]. The authors also reported deep vein thrombosis in 58% [15] . Reports of lower rates of VTE in patients with COVID-19 compared to our cohort might be explained by different thresholds to perform diagnostic tests such as CTPA or different disease severities. In our cohort, 31% (5/16) patients required VV-ECMO compared to 8% in other studies [7] .The severity of COVID-19 pneumonia in our collective is also reflected by the fact, that only 8% of all lung segments evaluated by CT appeared to have unaffected parenchyma.

Pulmonary embolism or pulmonary artery thrombosis?

Several findings suggest the thrombi detected by CTPA in COVID-19 could -at least in part -be locally formed by the mechanism of thromboinflammation [16] SARS-CoV-2 is known to cause coagulopathy [8] [17, 18] . By mediating endothelial dysfunction and systemic inflammation, the coronavirus can cause a procoagulant state [19] . In addition, any acute respiratory distress syndrome (ARDS) can cause pulmonary thrombus formation. Endothelial damage will begin in the microvasculature and might extend as local process mediated by pro-inflammatory signals [20] Autopsy studies showed microthrombi in alveolar capillaries in 5/11 COVID-19 patients [21] . Also, thrombi are found much more frequently in the lungs than in any other organ [7] , Limitations: Several limitations have to be considered when interpreting data presented here. First of all, we derived our data from a small patient collective. Since each individual segment was analyzed, a considerable number of segments could be registered. Still, data needs to be confirmed in a larger patient collective in order to prove a local clot formation. All patients were treated at a single medical intensive care unit. Decision to perform a CTPA was driven by judgement of the physicians in charge which could lead to an overestimation of rate of pulmonary artery thrombosis.

Several factors, such as ventilation or ECMO, negatively influenced image quality of the CTPA examinations especially limiting the analysis of peripheral pulmonary vessels. Even though 16/22 patients underwent CTPA, a selection bias cannot be excluded. Since only ICU patients were included, we cannot extrapolate the findings to a collective of mild to moderate COVID-pneumonia.

None of our patients had clinical evidence for a deep vein thrombosis. Still, we cannot exclude lower limb thromboembolism since lower limb venous duplex studies have not been routinely performed.

We acknowledge the preliminary nature of these findings, including its retrospective nature and limited sample size. Data presented here has therefore be considered hypothesis generating only.

Thrombi in segmental pulmonary arteries are common in COVID-19. All Segments occluded by thrombus were opacitated and no pulmonary embolus was detectable located in a segment without opacitation. This might suggest local clot formation. Quality of CTPA: The distribution of measured HU in the right and left main pulmonary arteries stratified according to subjective image quality is given in figure 1 . Lower image quality was associated with lower measured HU, P<0.05 for the comparison of image quality 2 and 3.

We did not observe a significant difference of standard deviation of measured HU when stratified by subjective image quality. Posterior basal (X) 0 2 12 2 3

Additional Table 2 Evaluation of parenchymal abnormalities and pulmonary embolism. Parenchymal abnormalities were grouped in non-consolidating changes, ground-glass opacities (GCO) and/or crazy-paving pattern, air space consolidation or consolidated areas as mixed-pattern. High antiXa target 0.4 -0.7 0 (0%) 0 (0%) 0 (0%) 1.000

Additional Table 3 Anticoagulation targets before PAT diagnosis in patients just bevor CTPA was performed in order to diagnose the PAT. High aPTT target>60 s 1 (4.5%) 0 (0%) 1 (9.1%) 1.000

Argatroban Low/medium aPPT target<60 1 (4.5%) 1 (9.1%) 0 (0%) 1.000

High aPTT target>60 s 1 (4.5%) 1 (9.1%) 0 (0%) 1.000 LMWH Low antiXa target <0.4 3 (13.6%) 1 (9.1%) 2 (18.2%) 1.000

High antiXa target 0.4 -0.7 0 (0%) 0 (0%) 0 (0%) 1.000

Additional Table 4 Anticoagulation targets in patients with and without venovenous ECMO just bevor CTPA was 

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in

CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV)

CT imaging features of 4121 patients with COVID-19: A metaanalysis

Chest CT findings of COVID-19 pneumonia by duration of symptoms

Quantitative computed tomography analysis for stratifying the severity of Coronavirus Disease

Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

High incidence of venous thromboembolic events

Imaging of acute pulmonary embolism: an update

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

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Coagulation disorders in coronavirus

SARS-CoV-1, MERS-CoV and lessons from the past

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis

Post-mortem examination of COVID19

Additional Table 1 Association of PE with normal and opacified segmental parenchyma. Abbreviations: PE pulmonary embolism; GGO ground-glass opacities.