key: cord-0954727-gfj1bqd7
authors: Kaminetzky, Mark; Moore, William; Fansiwala, Kush; Babb, James S.; Kaminetzky, David; Horwitz, Leora I.; McGuinness, Georgeann; Knoll, Abraham; Ko, Jane P.
title: Pulmonary Embolism on CTPA in COVID-19 Patients
date: 2020-07-02
journal: Radiol Cardiothorac Imaging
DOI: 10.1148/ryct.2020200308
sha: 9aae115a4deffc656f4db0ab462662d845fddda0
doc_id: 954727
cord_uid: gfj1bqd7

BACKGROUND: Understanding pulmonary embolism (PE) rate and contributing comorbid, clinical, laboratory, and imaging characteristics may aid in management of pro-thombotic events in COVID-19 (COVID+) patients. PURPOSE: To evaluate PE prevalence on computed tomography pulmonary angiogram (CTPA) in COVID+ patients and factors associated with PE severity. MATERIALS AND METHODS: A retrospective, single-center study evaluated 62 COVID+ patients who underwent CTPA between March 13 and April 5, 2020. A 62-patient cohort who underwent CTPA prior to the first reported local COVID-19 case was retrogradely selected. The relative rate of CTPA-positivity was recorded. For the COVID+ cohort, comorbidities, laboratory values, clinical outcome, and venous thrombosis were recorded. Two thoracic radiologists assessed embolic severity using the Mastora system and evaluated right heart strain. Statistical analysis evaluated factors associated with PE and arterial obstruction severity. A P-value<.05 was considered significant. RESULTS: 37.1% of COVID+ patients had PE, higher than 14.5% of pre-COVID patients (P=.007). D-dimer levels closest to CTPA date correlated with Mastora obstruction score. ROC analysis identified optimal sensitivity (95%) and specificity (71%) for PE diagnosis at 1394 ng/mL DDU. The mean D-dimer was 1774 ng/mL and 6432 ng/mL DDU in CTPA-negative and CTPA-positive subgroups, respectively (P<.001). One additional CTPA-negative patient had DVT, for a total 38.7% with PE/DVT, despite 40% receiving prophylactic anticoagulation. Other factors did not demonstrate significant PE association. CONCLUSION: 37.1% of COVID+ CTPA exams diagnosed PE. PE can be a cause of decompensation in COVID+, and D-dimer can be used to stratify patients regarding PE risk and severity.

1. CTPA was positive for pulmonary embolism in 37% of COVID-19 patients. 2. D-dimer levels directly correlate with the presence and extent of pulmonary embolism as indicated by the Mastora index and can be used to risk stratify patients for pulmonary embolism workup.

Patients with confirmed COVID-19 had pulmonary embolism diagnosed in 37% of CTPA examinations with D-dimer levels associated with the presence of pulmonary embolism and the degree of pulmonary artery obstruction.

The novel 2019 coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 began in December 2019 and by March 2020 reached pandemic levels (1) . Current guidelines through the American College of Radiology and the Centers for Disease

Control do not support routine screening for COVID-19 with imaging; rather nasopharyngeal or oropharyngeal swab for viral RNA testing is the recommended confirmatory test. This perspective is based on literature that demonstrates that chest computed tomography (CT) may be falsely negative early in the disease, with chest CT reserved for evaluation of complications (2, 3) .

Hypercoagulability has been reported in patients who have COVID-19 (COVID+), with increased mortality associated with elevated serum thrombogenic proteins such as D-dimer (4) .

In fact, patients with severe COVID-19 who were empirically treated with low-molecular weight heparin (LMWH) had a lower 28-day mortality compared with similarly-ill patients that were not treated with LMWH (5, 6) . This raises the question of whether thrombotic and embolic events worsen the patient's clinical status.

In particular, there is a heightened awareness of pulmonary embolism in COVID+ patients, which would diminish the already compromised pulmonary function and capacity.

Currently, a few case series (7) (8) (9) (10) (11) , clinical reports (12, 13) , and recent radiology research report letters in European cohorts have been published on pulmonary embolism, which is diagnosed using CT pulmonary angiography (CTPA) (14, 15) . Many acutely-ill and hospitalized COVID+ patients have multi-organ failure and possibly acute kidney injury (16) , and decisions as to I n p r e s s whether CTPA is performed take into consideration both the potential risk of nephrotoxicity from intravenous contrast administration and the benefit of diagnosing pulmonary embolism.

Therefore, an understanding of the frequency of pulmonary embolism and the relationship between D-dimer levels and the degree of pulmonary artery obstruction may aid in the diagnosis and management of this disease in COVID+ patients. Our objective was to determine the prevalence of pulmonary embolism on CTPA studies in a United States (US) cohort of COVID+ patients and identify clinical features associated with a positive CTPA exam, pulmonary artery obstruction severity, and outcomes.

The study was approved for an exemption by the institutional review board (IRB).

Written informed consent was waived by the IRB. The study was a Health Insurance Portability and Accountability Act-compliant retrospective review of pertinent clinical and imaging data on consecutive CTPA studies at NYU Langone Health and affiliated hospitals. Two cohorts are detailed below.

This is a single-institution retrospective study in which the radiology information system was queried (Primordial, Nuance Communications, Inc., Burlington, MA) by a radiology resident (MK) using search terms of "pulmonary embolism" to identify CTPA examinations performed between March 13, 2020 and April 5, 2020. The electronic medical record (EMR) (Epic, Verona, WI) for these patients was reviewed to identify those who had COVID- 19 

Chest CTPA protocol at our institution entailed intravenous administration of 300 mg/mL of iodinated contrast at 3 to 5 mL per second with timing optimized for the pulmonary artery using bolus tracking and automatic triggering. Imaging was performed after a small Discrepancies were resolved by consensus between the two radiologists. For each patient, a total score was generated by summing the obstruction score of every vessel evaluated, and an obstruction ratio for all arteries was generated by dividing the total score for each patient by The presence of right heart strain on CT, as indicated by the right ventricular (RV)/left ventricular (LV) ratio > 1, contrast reflux into the inferior vena cava to the hepatic veins and coronary sinus, and degree of septal bowing toward the LV, was recorded. For the RV/LV ratio, the maximal dimensions of the RV and LV chambers were obtained by measuring perpendicularly from inner aspect of free wall to inner aspect of the interventricular septum (19) . Consensus was obtained for discrepancies between the two readers. If either the CTPA or the echocardiogram demonstrated right heart strain, the patient was considered as positive for right heart strain. 

The COVID+ cohort was composed of 62 patients with 40 men and 22 women, mean age of 57.8 +/-(SD) 13.9 years (range of 28-89 years) with men having mean age of 55.5 +/-(SD)

13.6 years and women mean 61.9 +/-(SD) 13.8 years (Table 1 ). In the COVID+ cohort, 37.1% (Table 1) , respectively. In terms of the CTPA positive and CTPA negative COVID+ cohorts (Table 1) Table 1 ). Of these features, a greater percentage of patients were female P=.002) and had coronary artery disease (P=.016) in the pre-COVID patients than the COVID+ cohort (see Supplemental Table 1 Table   2 ). Two of 10 patients (20.0%) who were CTPA positive and had right heart strain expired, whereas none of the CTPA positive patients who did not have right heart strain expired (Supplemental Table 2 ). None of the CTPA positive patients with right heart strain on echocardiogram and/or CTPA had a preexisting echocardiogram within one year prior to the COVID+ hospitalization.

ObstCenRatio, ObstTotRatio, and the RV/LV ratio did not differ significantly between the patient gender, preexisting conditions, and clinical outcome for each metric of pulmonary embolism severity (P>.05) (Supplemental Table 3 There was a statistically significant and positive correlation between both ObstCenRatio (P=.007), and ObstTotRatio (P=.002) with D-dimer levels ( Pulmonary embolism in COVID+ patients has been described only recently, beginning with single case and small-series reports (7-9) (10, 11). Our study findings supported two recently published radiology research letters describing 23% (14) and 30% (16) Also, a majority of the emergency department CTPA exams are interpreted by thoracic radiologists at our institution, and thus, the effect of interpreter expertise is minimized ( (23)).

Recent literature in COVID-19 has reported thrombosis secondary to the COVIDassociated vascular injury (26, 27) . It is difficult to reliably distinguish between thrombus formation and embolism on CTPA. We did not specifically evaluate whether the central CTPA intravascular defects extended to distal subsegmental vessels. Our COVID-19 cohort had a higher rate of DVT (53%) compared to 29% in our pre-COVID cohort, suggesting a thromboembolic component for the intravascular defects on CTPA, though this difference was not statistically significant, possibly due to small numbers. Given the association of COVID-19

with a hypercoagulable state, prophylactic anticoagulation has been studied and shown to decrease mortality (6) , and the role of empiric prophylactic and therapeutic anticoagulation needs elucidation (28) . respectively. This correlation between D-dimer and pulmonary embolism is well buttressed by the existing literature (33, 34) , although a number of causes for D-dimer elevation exist that we did not specifically analyze, including DIC from multiple etiologies, pregnancy, age, and cancer (35) . However, our investigation raises the possibility of risk stratification according to D-dimer value for pulmonary embolism in COVID+ patients. A 500 ng/mL value is used as a threshold for D-dimer positivity in the general population (33) . Our study demonstrated that a D-dimer value of 1394 ng/mL provided a sensitivity of 95% and a specificity of 71% for pulmonary embolism in our COVID+ cohort. When including the patient who had a DVT but a negative CTPA, the rate of thromboembolic disease increased to 38.7%. This may aid in identifying those patients with higher likelihood of pulmonary embolism and determining those who should be considered for CTPA, particularly given the need to minimize in hospital transmission of COVID-19 to other patients and staff.

Most of the other demographic, comorbid, laboratory, clinical, and imaging features did not differ significantly between the CTPA positive and negative subgroups. A history of diabetes was the only comorbidity that was significantly less frequently observed in the CTPA positive I n p r e s s cohort, which may possibly be attributed to our relatively small sample size (only 3/23 patients with pulmonary embolism had diabetes). Additionally, the inflammatory marker ESR was inversely associated with the severity of pulmonary embolism as evidenced by ObstCenRatio and the ObstTotRatio. This may reflect our small sample size of 10 CTPA positive patients who had an ESR value. The proportion of abnormal lung parenchyma thought to be related to COVID (COVIDLungRatio) was inversely proportional to the presence of RV/LV ratio. An explanation for this association is not clear, and this finding may also be related to our small numbers. In terms of outcome, we did not identify a significant mortality difference between the CTPA positive and negative cohorts (8.7% versus 12.8%), which could reflect diagnosis and treatment of pulmonary embolism although is unclear given our small numbers. Compared to our pre-COVID cohort, COVID+ patients had a significantly higher fraction of men, which may result from men associated with worse prognosis and higher mortality. It is unclear why a lower proportion of coronary artery disease was seen in the COVID+ patients compared to the pre-COVID group. Possibly more pre-COVID patients who had coronary artery disease and chest pain may have undergone CTPA due to overlapping clinical presentations than patients in the COVID+ cohort.

There has been association of better outcomes of COVID+ patients treated with anticoagulation prophylaxis, such as low molecular weight heparin in sepsis induced coagulopathy and high D-dimers (5, 28) . Awareness and identification of thromboembolic complications such as pulmonary embolism may aid in improving outcomes as diagnosed patients would be treated with anticoagulation.

As discussed, a major limitation of our study is the relatively small sample size. Also, COVID-19 in our cohort may have raised the threshold of health care professionals for ordering CTPAs, given concerns pertaining to the contamination of CT scanners and in-hospital transmission of disease, thus elevating the proportion of positive examinations. Conversely, critically-ill patients with pulmonary embolism may not have had CTPA due to their being ventilated and unstable clinical status. Furthermore, many patients with ultrasound-confirmed peripheral venous thrombosis may not have had CTPA. Also, we compared the CTPA positivity rate in COVID+ patients to that of a cohort prior to COVID-19 that was not specifically matched for demographic, comorbid, or laboratory data, including D-dimer values and serves as a basis for future investigations. This may entail correlation of D-dimer levels with pulmonary artery severity and comparison between these two cohorts. We cannot exclude the possibility that undetected COVID-19 was present in the geographic population before March 1, 2020. Despite these aspects, an increased rate of thromboembolic events, pulmonary embolism, and derangements in coagulation factors in COVID+ patients has been supported by recent literature and is higher than that reported in ICU patient cohorts (12) (13) (14) (15) 24) . Additionally, due to the retrospective design of our study, many patients lacked laboratory testing of coagulation and inflammatory markers during their workup, limiting our evaluation of values such as for fibrinogen, ferritin, and ESR; echocardiography; and understanding for ordering CTPA. Also, echocardiography is subject to observer variation (36) . Another limitation is that we cannot ascertain whether right heart strain was acute or preceded the current clinical presentation.

However, none of the investigated COVID+ CTPA-positive patients with right heart strain on CTPA or echocardiogram had echocardiograms in the year prior to the COVID+ hospitalization, I n p r e s s so right heart strain chronicity cannot be reliably ascertained. Some of the patients' final clinical outcomes have not been established due to the short time frame between pulmonary embolism CTPA and data collection for this study. Nasopharyngeal PCR testing was the gold standard for determining COVID-19 infection; however, the test is not 100% sensitive (37) .

Thus, the true rate of pulmonary embolism may be higher in our network as there may have been patients with positive CTPA studies who were not identified to be COVID+. Additionally, as mentioned previously, chest CT was not performed routinely for initial diagnosis of COVID-19, and our patient population may have reflected those with more severe lung involvement.

Thus, we were unable to address vascular enlargement proposed by other investigators (29, 30) as a sign in early COVID-19 infection. Future investigation with a larger cohort may elucidate influencing factors for pulmonary embolism.

In conclusion, 37.1% of the CTPA examinations were positive for pulmonary embolism in a US cohort of COVID+ patients. We have demonstrated that D-dimer levels differed significantly between CTPA positive and negative studies and correlated with the severity of pulmonary artery obstruction. This supports the growing understanding that hypercoagulable events are elevated in COVID+ patients, and these patients are at increased risk for pulmonary embolism. Pulmonary embolism should remain a primary differential consideration for all COVID+ patients exhibiting acute or subacute respiratory distress. D-dimer levels can potentially be used to risk stratify patients in terms of suspicion for pulmonary embolism and severity.

I n p r e s s I n p r e s s I n p r e s s CAD 0 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/ I n p r e s s 

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CAD: Coronary artery disease; COPD: Chronic obstructive pulmonary disease; DVT: Deep venous thrombosis