key: cord-335108-5u3578ws authors: Fang, C.; Garzillo, G.; Batohi, B.; Teo, J.T.H.; Berovic, M.; Sidhu, P. S.; Robbie, H. title: Extent of pulmonary thromboembolic disease in patients with COVID-19 on CT: relationship with pulmonary parenchymal disease date: 2020-07-10 journal: Clin Radiol DOI: 10.1016/j.crad.2020.07.002 sha: doc_id: 335108 cord_uid: 5u3578ws Abstract Aim To report the severity and extent of pulmonary thromboembolic disease (PTD) in COVID-19 patients undergoing computed tomography pulmonary angiography (CTPA) in a tertiary centre. Materials and methods This is a retrospective analysis of COVID-19 patients undergoing CTPA over a period of 27 days. The presence, extent, and severity of PTD were documented. Two observers scored the pattern and extent of lung parenchymal disease including potential fibrotic features, as well as lymph node enlargement and pleural effusions. Consensus was achieved via a third observer. Interobserver agreement was assessed using kappa statistics. Student’s t-test, chi-squared, and Mann–Whitney U-tests were used to compare imaging features between PTD and non-PTD sub-groups. Results During the study period, 100 patients with confirmed COVID-19 underwent CTPA imaging. Ninety-three studies were analysed, excluding indeterminate CTPA examinations. Overall incidence of PTD was 41/93 (44%) with 28/93 patients showing small vessel PTD (30%). D-dimer was elevated in 90/93 (96.8%) cases. A high Wells’ score did not differentiate between PTD and non-PTD groups (p=0.801). The interobserver agreement was fair (kappa=0.659) for parenchymal patterns and excellent (kappa=0.816) for severity. Thirty-four of the 93 cases (36.6%) had lymph node enlargement; 29/34 (85.3%) showed no additional source of infection. Sixteen of the 93 (17.2%) cases had potential fibrotic features. Conclusion There is a high incidence of PTD in COVID-19 patients undergoing CTPA and lack of a risk stratification tool. The present data indicate a higher suspicion of PTD is needed in severe COVID-19 patients. The concomitant presence of possible fibrotic features on CT indicates the need for follow-up. . Since then, the virus has spread rapidly worldwide and as of 8 May 2020, there are over 3.7 million reported cases of COVID-19 globally with over 260,000 deaths (2) . The majority of patients with COVID-19 present with an acute respiratory illness of varying severity with fever, cough, and dyspnoea being the most common symptoms (3, 4) . The diagnosis of COVID-19 is usually confirmed by identification of viral RNA using reverse-transcription polymerase chain reaction (RT-PCR); however, the RT-PCR test is subject to variability depending on sampling technique with positive detection rate ranging between 30-60% (5) . Hence, imaging has become an important tool in the diagnosis and management of patients with COVID-19, initially prompted by findings of a study by Ai et al. (6) confirming high sensitivity of computed tomography (CT) in diagnosing COVID-19; however, the use of CT as a first-line imaging technique remains controversial and in most radiology departments, CT is reserved for cases with severe disease or those with stagnating or deteriorating clinical conditions (7) (8) (9) . In the wake of the pandemic, various radiological societies and colleges have set guidance on how to interpret the pattern and extent of radiographic and CT findings in patients with suspected or confirmed COVID-19 (10-13); however, none of the existing guidance has been externally validated in larger cohorts. In addition, despite several reports investigating the relationship between poor outcomes and various clinical and biochemical factors (3, 4, 14, 15) , the focus on radiological parameters remains somewhat limited. Coagulopathy is emerging as one of the common complications of COVID-19 (16, 17) and several reports have concluded that high D-dimer values, prolonged prothrombin time, and thrombocytopenia are associated with poor outcome (3, 15, (18) (19) (20) (21) (22) . The pathophysiology is not well understood, but emerging evidence points towards hyperinflammation resulting in a vascular disease within the lungs that is primarily characterised by thrombotic microangiopathy (22, 23) . Recently published data in a small cohort of hospitalised patients with severe COVID-19 suggest up to 40% incidence of pulmonary thromboembolic disease (PTD) (24, 25) . The recent report from the National Institute for Public Health of the Netherlands concluded that the thrombotic state can occur in a substantial percentage of COVID-19 patients, but highlighted the paucity of data on the prevalence of PTD (26) . The aim of the present study was to report the severity and extent of PTD in patients with confirmed COVID-19 who have undergone CTPA imaging in a tertiary centre. The secondary aims are (1) to assess the effectiveness of the British Society of Thoracic Imaging (BSTI) current guidance on the pattern and extent of lung parenchymal abnormalities in COVID-19, and (2) to assess whether there is any difference in the patterns and severity of pulmonary parenchymal disease on CT in COVID-19 patients with and without PTD. A single-centre retrospective analysis of all consecutive patients with confirmed SARS-CoV-2 on RT-PCR who underwent a CT pulmonary angiography (CTPA) study between 23 March 2020 and 19 April 2020 was performed. This project was granted approval by the institutional Ethics committee. Patient consent was not required due to retrospective nature of the study. All CT examinations were acquired using a GE Discover 750 HD (64 section) CT machine (GE Healthcare) using the departmental COVID-19 CTPA protocol for PTD (1.25 mm section thickness, peak tube voltage of 100kVp, and current modulation range between 80-500 mAs, tube rotation time of 0.5 seconds, and a pitch of 0.984:1) which includes a volumetric non-contrast high-resolution CT thorax prior to intravenous administration of 60 ml non-ionic contrast medium with 100 ml saline chaser at a rate of 4.5 ml/s with a time delay of 6 seconds, using a bolus-tracking technique, set at the pulmonary phase. All patients were scanned in a supine position from lung apices to bases at full inspiration. All images were reconstructed using a high-spatial-frequency soft kernel (WW/WL 400/40, 0.625 mm sections). Contiguous images of 1-mm thickness were reviewed on lung window settings for parenchymal disease (width,1,500 HU; level, -500 HU) and at mediastinal window settings for PTD and lymph node enlargement (width, 350 HU; level, 50 HU). The unenhanced thoracic CT was performed to accurately assess subtle parenchymal abnormalities, such as ground-glass infiltrates, that can be masked by contrast medium. Patient demographic, clinical, laboratory, and outcome data were extracted from electronic medical records. Laboratory data collected were from the date closest to the CTPA study date. Duration of clinical symptoms was defined from the selfreported onset of COVID-19 symptoms to the date of CTPA. Wells' scores for PTD were calculated (27) . Outcome data were updated until 3 May 2020, which was 2 weeks after the end of study inclusion period. All CT studies were reviewed by two experienced radiologists (with 4 years of experience in cancer imaging and with 6 years of experience in thoracic imaging, respectively). CT patterns and severity of lung parenchymal disease, severity and extent of PTD, presence of CT signs of pulmonary hypertension, CT features of possible fibrosis, and intrathoracic lymph node enlargement were reviewed. A consensus was reached by a third radiologist (11 years of experience in thoracic imaging) where there was a disagreement. All readers were blinded to patient clinical details and existing radiology reports. CT pattern and the extent of parenchymal disease was documented as normal, classic, probable, indeterminate or non-COVID-19, and mild, moderate, and severe, respectively, as per BSTI guidelines ( Table 1 ). The CT severity was defined as mild if up to three focal abnormalities of 3 cm in maximum diameter. Severity of PTD was classified as subsegmental, segmental, lobar, main, and saddle. The extent of PTD was documented based on the number of pulmonary lobes involved (between 1-6); with lingula considered a separate lobe. Potential features of fibrosis were considered present if two of the following were observed: traction bronchiectasis away from the areas of consolidation but within the areas of ground-glass opacification, volume loss as judged by position of the oblique fissures (28) , and architectural distortion as per Fleischner Society glossary of terms (29) . The patterns of potential fibrosis on CT were categorised into possible fibrotic organising pneumonia or possible fibrosis associated with acute respiratory distress syndrome (ARDS), also based on Fleischner Society glossary of terms (29) . Intrathoracic lymph nodes were considered enlarged if they measured >10 mm or >3 mm in short axis diameter for mediastinal and hilar lymph nodes, respectively (30) . CT signs of pulmonary hypertension was defined as pulmonary artery diameter >30 mm, pulmonary artery diameter to ascending thoracic aorta ratio >1, and contrast medium reflux into the inferior vena cava/hepatic veins (31) . Statistical analysis was performed by using SPSS software (version 23; IBM, Chicago, IL, USA), and p-values <0.05 were considered to indicate statistical significance. The normality of data was assessed using the Shapiro-Wilk test. Continuous variables were reported as mean±standard deviation or median (interquartile range) as appropriate. kappa statistics were used to assess interobserver agreement with the level of agreement classified as: poor (kappa <0.40), fair (0.4<kappa<0.6), good (0.6<kappa<0.75), excellent (0.75<kappa<1.0) (33) . Student's t-test, chi-squared test, Mann-Whitney U-test where appropriate were used to compare study parameters between the groups based on the normality of the data. Patent demographics, clinical, laboratory data within PTD and non-PTD subgroups There were 2,157 patients with positive RT-PCR tests for SARS-CoV-2 during the study period (Fig. 1) . Out of 297 patients referred for CT imaging, 100 CTPA studies were performed in 97 COVID-19 patients. Seven studies were excluded from final analysis due to non-diagnostic quality. CTPAs were referred from the emergency department (n=24/93), inpatient wards (n=49/93), and intensive care units (n=20/93). Patient demographic, clinical and laboratory, and outcome data are listed in Table 2 . D-dimer was elevated in 90/93 (96.8%) of study cases. The median duration of symptoms to CTPA studies in patients referred from the emergency department, inpatient wards, intensive care unit was 8.5, 16, and 21 days, respectively, and the overall median duration of symptoms to CTPA studies was 14 days. The overall incidence of PTD was 44% (n=41/93). In 12/24 (50%) referrals from the emergency department, the studies were positive for PTD, 16 (Fig. 3) . In 16/93 (17.2%) studies, imaging demonstrated at least two CT signs of possible fibrosis. In 13 (81.3%) of these cases, the specific pattern of potential fibrotic features on CT was in keeping with fibrotic organising pneumonia rather than possible fibrosis related to ARDS (Fig. 4 ). There were 34/93 (36.6%) cases with enlarged mediastinal or hilar lymph nodes. The distribution of lymph node enlargement and pleural effusion among different CT patterns is detailed in Table 4 The presence of pulmonary hypertension was significantly more common among patients with PTD. The level of D-dimer was significantly higher in patients with severe parenchymal disease compared with moderate disease (p=0.046). The lymph node status and presence of pulmonary fibrosis did not differ among the PTD and non-PTD subgroups (Table 4 ). The present study has confirmed the high incidence of PTD in COVID-19 patients who underwent CTPAs. In the pre-COVID-19 period, the detection rate of PTD was 4.2% in the emergency setting without risk stratification and 11.2% with Wells' score risk stratification (34) , whereas, in the present COVID-19 cohort, PTD is not only common, but the Wells' score was not discriminatory in estimating the risk of PTD. This is likely due to Well's scoring being weighted towards PTD as the leading diagnosis rather than a secondary diagnosis concurrent with symptomatic lung disease. Although conventional D-dimer thresholds was non-discriminatory for PTD (as The recommended UK-wide guidance at the time of our study was published by BSTI, which is based on expert consensus rather than real world data. We used the BSTI guidance for characterisation of the CT patterns and the extent of disease on the basis of our current clinical practice as opposed to the more recently introduced reporting systems such as CO-RADS (40). In the present cohort, better interobserver agreement was found using BSTI guidance in comparison with reported kappa values of 0.47 for CO-RADS system; however, the present results showed that interobserver agreement for the patterns of parenchymal abnormalities was at best moderate, indicating that BSTI guidance may require revision with more specified definitions for disease patterns. It should also be noted that the majority cases in the present cohort had moderate to severe disease, which could mask A large proportion of patients with COVID-19 were found to have enlarged intrathoracic lymph nodes, which is in distinction to the initial report from China suggesting only 6% incidence of lymph node enlargement in hospitalised patients (41). Recent correspondence by French investigators (42) showed up to 66% incidence of lymph node enlargement in COVID-19 patients admitted to intensive care unit. This indicates controversy surrounding the issue of lymph node enlargement, which could be partly due to differences in study cohorts. No coexisting pathogens were found that could explain lymph node enlargement in the majority of the cases, nor can the size of the lymph nodes be attributed to the presence of fibrosis. Similarly, pleural effusion is regarded as a non-COVID-19 feature (12); however, this is also relatively common in the present cohort of confirmed COVID-19 cases, but may be a feature of comorbidities. There are limitations to the present study. The sample size is relatively small, and the data were collected retrospectively comprising patients admitted to hospital, which result in selection bias of patients with more severe disease. 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