To Study the Correlation of Clinical Severity and Cytokine Storm in COVID-19 Pulmonary Embolism Patients by Using Computed Tomography Pulmonary Angiography (CTPA) Qanadli Clot Burden Scoring System

Background: Pulmonary embolism (PE) is a fatal form of venous thromboembolism (VTE), with an overall untreated mortality of up to 30%. Greater than 50% of patients with lower extremity proximal DVT have concurrent PE at presentation. VTE has been seen in up to one-third of patients with COVID-19 infections requiring intensive care unit (ICU) admission. The objective of this study is to determine the correlation between CT pulmonary angiography, pulmonary embolism clot burden, and the Qanadli scoring system with clinically severe COVID-19 pneumonia and cytokine storm. Material and Method: 153 COVID-19 hospitalized patients who underwent CT pulmonary angiography (CTPA) for likely PE on pretest probability modified Wells criteria were enrolled. COVID-19 pneumonia was classified as URTI (upper respiratory tract infection), mild, severe, and critical COVID pneumonia. For data analysis, we categorized into two groups: (1) the non-severe group included URTI and mild pneumonia, and (2) the severe group included severe and critical pneumonia. We used the Qanadli scoring system to assess the PE percentages of pulmonary vascular obstruction using CTPA. Results: 41.8% (64) of COVID-19 patients were diagnosed with pulmonary embolism (PE) on CTPA. The majority of 51.6% of pulmonary vascular occlusions using the Qanadli scoring system for pulmonary embolism were at segmental arterial levels. Out of 104 COVID-19 cytokine storm patients, 45 (43%) were associated with pulmonary embolism. Overall, a 25% (16) mortality rate was observed in COVID-19 patients with pulmonary embolism. Discussion: The pathogenesis of hypercoagulability in COVID-19 may include direct endothelial cell invasion by the virus, microvascular inflammation, endothelial exocytosis, and endotheliitis. A meta-analysis of 71 studies to investigate the occurrence of PE on CTPA in COVID-19 patients found 48.6% in ICU settings and 65.3% of patients have clots in the peripheral pulmonary vasculature. Conclusions: There is a significant correlation between pulmonary embolism and high clot burden Qanadli CTPA scores, as well as between the severity of COVID-19 pneumonia and mortality. The association between critically ill COVID-19 pneumonia and pulmonary embolism may result in higher mortality and a poor prognostic marker.


Introduction
Pulmonary embolism (PE) may be an occasionally fatal form of venous thromboembolism (VTE). The overall incidence of PE is approximately 112 cases per 100,000, increases with age, and is somewhat more common in males than females [1,2]. PE refers to partial or complete obstruction of the pulmonary artery or one of its branches by material such as a thrombus, tumor, air, or fat that originated somewhere else in the body. PE may be classified as acute, subacute, chronic, hemodynamically unstable, or stable, and by anatomic location such as saddle, lobar, segmental, and sub-segmental [3][4][5].
The pathogenesis of PE included endothelial injury, a hypercoagulable state, and venous stasis (Virchow's 1, 2 3 4 5 5 5 5 5 5 6 triad). Most PE arises from the proximal veins of the lower extremities (popliteal, femoral, and iliac), and more than 50% of proximal deep vein thrombosis (DVT) patients have coexisting PE at the time of presentation [6][7][8][9][10]. In most cases, PE is typically multiple, with the lower lobes being involved [11]. A series of pathophysiologic changes may occur once a thrombus lodge in the lung, including pulmonary infraction, impaired gas exchanges, and cardiovascular compromise with right heart failure [12][13][14]. The most common symptoms of PE are dyspnea, followed by pleuritic chest pain, coughing, and the sign of DVT. The lifethreatening PE may require thrombolysis, inferior vena cava filters, and embolectomy in addition to anticoagulation.
VTE is common in up to one-third of critically ill COVID-19 patients, even on prophylactic anticoagulation [15]. The disseminated intravascular coagulation (DIC)-like the state is referred to as a COVID-19-associated hypercoagulable state [16,17]. VTE prophylaxis is the standard of care in all COVID-19 hospitalized patients and intensive care units (ICU) unless there is a contraindication to anticoagulation.
The primary objective of this study is to determine the correlation between the percentage of PE clot burden by using the Qanadli scoring system for pulmonary vascular obstruction in CTPA and the clinical severity of COVID-19 pneumonia, and the secondary objective is to assess the correlation between the percentage of PE clot burden in CTPA and cytokine storm.

Materials And Methods
This is an observational, cross-sectional, retrospective cohort study of charts/data reviews of COVID  (2) the severe group included severe and critical pneumonia. Patients' data/electronic charts were reviewed by a trained physician, and baseline investigations, including chest X-ray, inflammatory markers (Ferritin, CRP, D-dimer, interleukin-6 (IL-6)), the comprehensive metabolic panel (CMP), and CT pulmonary angiography findings, were recorded on a dedicated MS Excel (Redmond, USA) datasheet. Images were reviewed by a consultant radiologist on a radiology workstation in settings for pulmonary vasculature and lung parenchyma. The presence or absence of occlusive or non-occlusive right ventricle thrombus, main pulmonary artery trunk, right or left pulmonary artery, inter-lobar pulmonary artery, lobar, segmental, sub-segmental, and intralobar arteries were recorded. All CT pulmonary angiograms were read by a consultant radiologist, and PE clot burden scores were calculated for all PE-positive CT pulmonary angiograms. We used the Qanadli scoring system based on the site of obstruction and the degree of occlusion of the pulmonary arteries. According to the Qanadli scoring system, the pulmonary arterial tree of each lung is regarded as having 10 segmental pulmonary arteries (three to the upper lobes, two to the middle lobe or lingula, and five to the lower lobes). The presence of an embolus in a segmental pulmonary artery is scored as 1 point, and emboli at the most proximal arterial level have a score equal to the number of segmental pulmonary arteries arising distally. To provide additional information on the residual perfusion distal to an embolus, a weighting factor is used for each value (0=no defect, 1=partial occlusion, 2=complete occlusion). An isolated sub-segmental embolus is considered a partially occluded segmental pulmonary artery and is assigned a value of 1. The maximum CT PE clot obstruction index is 40. The CT pulmonary angiogram severity score is based on the percentage of the obstructed surface of pulmonary arteries and used on a four-point scale (1=0-24%, 2=25-49%, 3= 50-74%, 4=75-100%). The data were collected from the electronic patient record system (Cerner) on a predesigned MS Excel (Redmond, USA) data collection sheet by a dedicated team.
This study aims to determine the mortality rate in COVID-19 patients with PE clot burden severity by using the Qanadli scoring system. Descriptive statistics are used to summarize and determine the sample characteristics and distribution of various considered parameters related to demographic, diagnostic, clinical, follow-up outcome measures, and other related features of such patients. The normally distributed data and results were reported with a mean and standard deviation (SD) with a corresponding 95% confidence interval (CI); the remaining results were reported with a median and interquartile range (IQR). Categorical data are summarized using frequencies and percentages. Associations between two or more qualitative variables were examined and assessed using Pearson Chi-square and Fisher Exact tests, as appropriate. Unpaired-T test and ANOVA were used to compare the mean values of different quantitative parameters between two or more groups. The correlation between various outcomes measured and evaluated quantitatively is calculated by Pearson or Spearman rank-order correlation. Appropriate regression analysis was performed to assess the effects of various factors and co-variates on primary outcome measures. Pictorial presentations of the key results were made using appropriate statistical graphs.
A two-sided p-value of <0.05 is statistically significant. All statistical analyses were done using IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.

Results
A total of 153 COVID-19 hospitalized patients who were suspected of PE and had a CT pulmonary angiogram performed were enrolled in this study. Demographic and clinical characteristics are shown in Table 1.   (12) being pre-diabetic, 6.6% (10) being chronic kidney disease (CKD), 6.6% (10) being ischemic heart disease (IHD), 3.9% (six) being asthmatic, and 2.6% (four) being smokers ( Table 1). According to the American Thoracic Society guidelines for community-acquired pneumonia (CAP), 83% of patients (127) were critically ill, 11.7% (18) had severe pneumonia, and 5.3% (eight) had mild pneumonia. Wells' Criteria for risk stratifies for PE pre-test probability of likely was 85.6% (131) and unlikely was 14.37% (22) with an odd ratio (OR) of 2.79. CT pulmonary angiography showed that 41.8% (64) patients were positive for pulmonary embolism, and 23.53% (36) had bilateral pulmonary embolism ( Table 2). In the CT pulmonary angiogram, 51.6% (33) were vascular occlusions at the pulmonary segmental arteries levels, 10.9% (seven) were sub-segmental arteries level, 10.9% (seven) were pulmonary artery levels, 6.3% (four) were lobar arteries levels, 3.1% (two) were inter-lobar arteries levels, and 1.5% (one) were clots at the main pulmonary trunk level, as in descending order ( Table 2). According to the Qanadli scoring system for PE obstruction and degree of occlusion of pulmonary arteries, the majority of pulmonary embolisms involved lower lobe segmental pulmonary arteries. In this study, the CT pulmonary angiogram obstruction severity score is based on the percentage (%) of obstruction of the pulmonary arteries. In this study, the percentage of pulmonary obstruction severity scores from 0% to 24% was 78.1% (50), from 25% to 49% was 10.9% (seven), from 50% to 74% was 6.3% (four), and from 75% to 100% was 4.68% (three). The majority of Qanadli scoring systems for PE obstruction severity scores in percentages from 0% to 24% were 78.1% (50) (  CT pulmonary angiography for pulmonary embolism at different pulmonary arterial systems and Qanadli scores for the degree of occlusion of the pulmonary arteries in percentages (%). Figure 1 of CTPA showed pulmonary embolism in bilateral main pulmonary arteries extending into all lobar and their multiple segmental branches (as shown with a red arrowhead) and bilateral patchy ground glass opacities.

FIGURE 1: CTPA showed PE in bilateral main pulmonary arteries and extended lobar branches.
Bilateral pulmonary embolism in the main pulmonary arteries extends into all lobar arteries and their multiple segmental branches. Serum lipase (>180 u/l associated with acute pancreatitis) 10 6.6% HbA1c (values equal and greater >12 associated poor control DM) 5 3.3%

TABLE 3: Laboratory features for severe COVID-19 and other multiorgan system involvement.
Various laboratory parameters such as LDH, ferritin, CRP, D-dimer, and IL-6 associated with the severity of COVID-19 infection and other multiorgan system involvement were included.

Discussion
This is a retrospective cohort cross-sectional observational study of 153 COVID-19 hospitalized patients whose charts/data were reviewed and who underwent CT pulmonary angiograms for suspected PE. The majority of these hospitalized COVID-19 patients were critically ill (83%), with severe pneumonia (11.7%). 41.8% (64) of patients had pulmonary embolism on CTPA, and 23.5% (36) had bilateral pulmonary involvement. The odd ratio of 2.79 (OR) for likely PE on Wells' criteria for pretest probability risk for PE. In this study, according to the Qanadli CT pulmonary angiogram, PE obstruction severity scores from 0 to 24% were 78.1% (50). The majority of pulmonary embolisms were associated with a significantly high level of inflammatory markers and cytokine storm.
The overall mortality of pulmonary embolism patients, if left untreated, is around 30%. Similar to this study, the mortality rate of PE-positive COVID-19 patients was 25% (16). There may be several complex and varied coagulation abnormalities in COVID-19 patients that produce a hypercoagulable state. The pathogenesis of hypercoagulability in COVID-19 patients may be caused by direct endothelial cell invasion by the SARS-CoV-2 virus, leading to complement-mediated endothelial injury, microvascular inflammation, endothelial exocytosis, and endotheliitis [18][19][20][21]. Stasis of blood flow may be seen in all critically ill hospitalized and immobilized patients. Several changes in circulating prothrombotic factors, including elevated factor VII and fibrinogen, circulating prothrombotic microparticles, and neutrophil extracellular traps (NETs), have been reported in severe COVID-19 infection [22][23][24]. The elevated levels of degradation products of crosslinked fibrin, such as D-Dimer, have been observed to correlate with COVID-19 illness severity [25][26] [29]. Another qualitative and quantitative analysis of three studies comprising data from 437 patients did not show statistically and significantly higher mortality in critically ill COVID-19 patients and concurrent PE. However, overall mortality was higher [30].
In this study, the majority of pulmonary embolism patients were in intensive care units and had critical or severe COVID-19 pneumonia. One-fourth (25%, 16) of PE-positive COVID-19 patients died. There is a significant Pearson correlation between CTPA-PE and PE clot burden severity of Qanadli score in percentages (p <0.001), as well as between severity COVID-19 pneumonia and discharge (p <0.022) in Table  4. There was other multiorgan involvement in COVID-19 patients, including skeletal muscle injury, acute myocardial injury, acute kidney injury, acute liver injury, and acute pancreatitis, in descending order ( Table 3). There was no significant Pearson correlation between the severity of COVID-19 cytokine storm, PE clot burden severity, Qanadli score in percentages, and severe COVID-19 pneumonia.
The limitation of this study is retrospective observational data analysis. Enrolled patients were in intensive care units, and the majority had a critical illness (selection bias). In addition, in our study, the majority of patients were male.

Conclusions
In this retrospective observational study, there is a significant correlation between pulmonary embolism and high clot burden Qanadli CTPA scores, as well as between the severity of COVID-19 pneumonia and mortality. However, there was no significant correlation between high clot burden Qanadli CTPA scores, cytokine storm, and the clinical severity of COVID-19 pneumonia. These findings suggest that critically ill COVID-19 pneumonia with pulmonary embolism may have a higher mortality rate and a poorer prognostic marker in this cohort of patients. However, a large-scale study is warranted to further support our findings.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. IRB issued approval 01-21-415. Protocol ID MRC-01-21-415 entitled "Pulmonary Embolism Clot Burden in COVID-19 patients: To study the correlation with clinical Severity and cytokine storm." has been approved by MRC. Hamad medical corporation (HMC), Qatar. Written informed consent was obtained from legally authorized representatives before the study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.