key: cord-0933869-oc25csga
authors: Trunz, Lukas M.; Lee, Patrick; Lange, Steven M.; Pomeranz, Corbin L.; Needleman, Laurence; Ford, Robert W.; Karambelkar, Ajit; Sundaram, Baskaran
title: Imaging approach to COVID‐19 associated pulmonary embolism
date: 2021-05-24
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14340
sha: 35b5fb122e598b964c50c274509f700f8bd6cf89
doc_id: 933869
cord_uid: oc25csga

The novel coronavirus disease‐2019 (COVID‐19) illness and deaths, caused by the severe acute respiratory syndrome coronavirus‐2, continue to increase. Multiple reports highlight the thromboembolic complications, such as pulmonary embolism (PE), in COVID‐19. Imaging plays an essential role in the diagnosis and management of COVID‐19 patients with PE. There continues to be a rapid evolution of knowledge related to COVID‐19 associated PE. This review summarises the current understanding of prevalence, pathophysiology, role of diagnostic imaging modalities, and management, including catheter‐directed therapy for COVID‐19 associated PE. It also describes infection control considerations for the radiology department while providing care for patients with COVID‐19 associated PE.

The novel coronavirus disease-2019 (COVID- 19) illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic, and the number of cases and deaths continue to rise despite extensive measures. 1, 2 The most common symptoms at the onset of COVID-19 are respiratory tract infection with fever, cough, fatigue, and dyspnea. 3, 4 In a fraction of patients, there is deterioration into a severe systemic illness with multiorgan failure resulting in a hypercoagulable state and thromboembolic complications. 5, 6 Pulmonary embolism (PE) is a severe and common sequela of this hypercoagulability in patients with Our understanding of COVID-19 associated PE continues to evolve. We summarise the current knowledge regarding the prevalence, pathophysiology, diagnosis, and PE management in COVID-19 patients. We also review imaging-based considerations in managing these patients while balancing the challenges of this pandemic.

The overall annual incidence of venous thromboembolism (VTE) in the United States is estimated to be 1-2 per 1000 of the population, with mortality rates ranging between 10% and 30% within 30 days. 8 However, the prevalence of COVID-19 associated PE may be as high as 37.1% (Table 1 ). The incidence of PE in nonintensive care unit (ICU) patients ranges between 1.6% and 6.4%, 9, 10 while ICU patients have higher rates of 13.6%-26.6% [10] [11] [12] [13] [14] [15] [16] (Table 2) . Even among the patients managed in the ICU, COVID-19 patients (a study on 107 patients) had an absolute increased risk of PE of 13.1%-14.4% compared with other ICU patients with similar illness severity. 14 It is unclear if patients with COVID-19 illness associated PE have increased mortality. Several studies comparing COVID-19 patients with and without PE found no statistically significant mortality difference between the two groups, although mechanical ventilation and ICU admission rates may be higher in patients who also have COVID-19 associated PE. 9, 11, 15, [17] [18] [19] [20] [21] However, variable and small sample sizes, and nonuniform patient diagnostic and management policies, contribute to our limited understanding of the true prevalence and impact of PE in COVID-19 patients. [10] [11] [12] [13] Despite this uncertainty, there is understandable concern that COVID-19 illness combined with PE may result in worse outcomes than either entity alone. Future studies on larger and more balanced patient cohorts may clarify this.

The pathophysiology of COVID-19 associated PE may differ from other causes of PE. Studies on COVID-19 patients have demonstrated PE in central pulmonary artery locations (main and lobar pulmonary arteries) 13, 19, [21] [22] [23] [24] as well as in a peripheral distribution. 9, [25] [26] [27] [28] Lung autopsies of COVID-19 patients revealed microangiopathy of alveolar capillaries with 69%-91% of thrombi in segmental and subsegmental pulmonary arteries. 9, [25] [26] [27] [28] Interestingly, in patients with known PE, there is a lower incidence of deep vein thrombosis (DVT) (6.9%-13.6%) in COVID-19 patients 9,14,17 compared to non-COVID-19 patients (45%-70%). 9,14,17,25,26 Also, unlike non-COVID-19 patients, COVID-19 patients often lack many traditional risk factors and comorbidities for PE. 14, 17, 20 These observations have facilitated the theory that in situ microthrombi in the small peripheral pulmonary vasculature may play an important role in COVID-19 associated PE. 9, 27, 28 Thrombotic microvascular injuries have also been described in other organs (eg, kidneys and skin) despite adequate anticoagulation in COVID-19 patients. [28] [29] [30] In addition, lower extremity DVT was found in 85.4% of COVID-19 patients admitted to the ICU (study of 48 patients) despite prophylactic anticoagulation highlighting the severity of the hypercoagulable state. 31 Hence, researchers currently believe that the combination of microvascular thrombus and SARS-CoV-2 viral-induced endothelial damage leads to a systemic inflammatory reaction and progressive multisystem prothrombotic state, resulting in multiorgan failure and death. 32

The root cause of increased D-dimer levels in COVID-19 illness is unclear. Studies have shown that elevated D-dimer levels are sensitive in diagnosing PE in COVID-19 patients. 9, 11, [19] [20] [21] [22] [23] 27 Elevated serum D-dimer levels of >4000 ng/mL accurately predicted COVID-19 associated VTE when combined with clinical exam findings (sensitivity of 80% and specificity of 70%) for diagnosing DVT. 33 Similarly, Ddimer cut-off levels of 2660 and 1394 ng/mL were shown to have 100% and 95% sensitivity for diagnosing PE in COVID-19 patients.

However, similar to the non-COVID-19 patient population, elevated D-dimer levels lack specificity (67% and 71%) in detecting COVID-19 associated VTE. 20, 23 Hence, it is currently not recommended to use Ddimer levels to diagnose COVID-19 associated VTE, 34 or decide which patients should undergo imaging to diagnose PE. 35 However, similar to non-COVID-19 patients, normal D-dimer values can effectively rule out VTE in the context of low pretest probability. Elevated D-dimers may also predict adverse outcomes such as mechanical ventilation, ICU admission, and disease severity in patients with [36] [37] [38] Studies have also shown high bleeding complications in COVID-19 patients with elevated D-dimer levels (>2500 ng/mL), complicating anticoagulation strategies for these patients. 39 

Ventilation-perfusion (VQ) scintigraphy plays an essential role in the evaluation of PE in patients with contraindications for intravenous contrast administration (advanced renal failure with eGFR under 30 mL/min/1.73 m 2 or severe allergy to iodinated contrast material), young females, or large patients who cannot be scanned with computed tomography (CT). 41 However, in COVID-19 patients, the ventilation portion of the VQ may result in the airborne spread of COVID-19 due to aerosol leakage. Patients' cough may also worsen after inhalation of radiopharmaceuticals, further increasing this risk. 47, 48 As a result, multiple authors have suggested performing only a planar perfusion scan, perhaps How did you gather, select, and analyse the information you considered in your review?

• We searched PubMed using the terms "Pulmonary Embolism" and "COVID-19" or "SARS-CoV-2" or "coronavirus 2019" for studies published in the medical literature without a time limit.

• We manually searched the references of selected papers for additional relevant articles.

• We selected articles that only directly addressed PE in patients with COVID-19. Only articles written in the English language were included.

Message for the clinic: What is the "take-home" message for the clinician?

• COVID-19 illness is associated with a hypercoagulable state, predisposing patients to thromboembolic complications such as pulmonary embolism.

• CTPA is effective for the diagnosis of COVID-19 associated pulmonary embolism, but attention must be made for appropriate infection control and peripheral thromboemboli, unique to COVID-19.

• Other modalities such as ventilation-scintigraphy, extremity venous Doppler ultrasound, and chest ra- 

Chest CT helps evaluate patients with known COVID-19 pneumonia and related thoracic complications. 53, 54 Semi-quantitate CT assessment of pneumonia severity and serial lung changes over time may correlate with disease severity and outcomes. 55, 56 Typical imaging manifestations of COVID-19 pneumonia are bilateral peripheral ground-glass opacities without pleural effusions ( Figure 1) . 53, 54, 57, 58 Based on the illness state, consolidation and intralobular reticulations may also be present. 53, 57, 59 Studies report abnormal pulmonary vascular thickening ("thick vessel sign") within COVID-19 pneumonia opacities ( Figure 2C ). 60 transporting severely ill patients to the CT scanner suite and the renal impairment risks by administering potentially nephrotoxic intravenous contrast material prior to any CTPA. 65 There are also special considerations for CTPA in evaluating for PE in COVID-19 patients. As discussed earlier, small peripheral thrombi may be more prevalent in COVID-19. 9,25-28 Hence, evaluating the subsegmental pulmonary arteries on CTPA is essential using thin-collimation CT images. 66 Dual-energy CT iodine maps may offer incremental benefits by showing lung parenchymal perfusion defects (Figure 3 ). 67 Even in the absence of PE, dual-energy CT can offer useful information on disease severity. Quantitative perfusion mapping can highlight vasculopathy in COVID-19, and decreased perfused blood volume relative to pulmonary artery enhancement is associated with right ventricular dysfunction. 68 Finally, during a CTPA, delayed images through the pelvis and lower extremities may be considered to evaluate DVT, thereby avoiding additional studies. 69 

In patients with known PE, there is a lower incidence of DVT (6.9%-13.6%) in COVID-19 patients 9,14,17 compared to non-COVID-19 patients (45%-70%). 9, 14, 17, 25, 26 This difference may partly be explainable by a lack of universal screening for COVID-19 patients.

Clinical DVT prediction scores (CURB-65 score of 3 to 5 or Padua prediction score greater than or equal to 4) and elevated D-dimer levels can help stratify COVID-19 patients at risk for DVT who should undergo diagnostic imaging. 70 Compared to conventional F I G U R E 2 56-year-old man presented to the hospital approximately two weeks after testing positive for COVID-19. A, Chest radiograph shows peripheral ground-glass opacities as well as a wedge-shaped opacity in the right mid lung (arrowhead). B and C, CTPA shows a right lobar pulmonary embolism (white arrow, B) and peripheral parenchymal opacities with internal dilated small peripheral pulmonary vessels (black arrow, C). D, The lung window shows a peripheral wedge-shaped opacity (black arrow) in the right upper lobe indicating pulmonary infarction venography, the diagnostic sensitivity and specificity of ultrasound (US) to detect proximal DVT using compression is 90%-100%. 71 Currently, extremity venous Doppler US for DVT is recommended for symptomatic patients; however, a routine screening examination in asymptomatic patients is not recommended. Only in rare circumstances where a patient has high suspicion for PE but is unable to undergo CTPA should extremity US despite the absence of DVT symptoms be considered. 69 Bedside echocardiography may also help diagnose PE-associated findings such as right ventricular dilatation or dysfunction and intracardiac thrombus, indicating a clot-in-transit. 72 The risk of spread of infection to sonographers can be minimised with specific changes to extremity venous Doppler US examination. 33 Customising and abbreviating the US scanning protocol for DVT, limiting the use of colour Doppler, avoiding routine scanning of the calf veins, and limiting studies to patients with clinical suspicion for DVT such as elevated D-dimer levels or abnormal dead-space fraction (a method to measure anatomical and alveolar dead space) indicating PE are helpful. Whenever possible, deferral until the patient is less contagious can be considered. 33, 69, 73 

Adequate anticoagulation in COVID-19 patients appears to correlate with better outcomes in severe COVID-19 infections and a lower incidence of PE. 17 Increased pulmonary artery pressure resulting in cardiac dysfunction is the primary mechanism of morbidity in COVID-19 associated massive or submassive PE. 78 The goal of CDT is to improve cardiac output by reducing thrombus burden and restoring pulmonary perfusion. 79 Proposed algorithms for the treatment of PE in COVID-19 have closely reflected prior consensus guidelines for CDT. 37, 78, [80] [81] [82] [83] However, the multidisciplinary National Pulmonary Embolism Response Team Consortium advises a conservative approach leaning towards medical management, given the risk of nosocomial spread and uncertain benefits of invasive therapies. Invasive procedures, including CDT, should be considered for massive PE with contraindication to systemic thrombolysis and submassive PE with impending clinical decompensation and contraindication to systemic thrombolysis. Any planned intervention requires multidisciplinary discussion with benefit and risk analysis. 72 The decision to proceed with thrombectomy or mechanical thrombolysis in COVID-19 patients requires disease-specific considerations. Single session thrombectomy (Figure 4 ) will reduce the F I G U R E 5 55-year-old man with a negative viral test but highly suspicious changes on chest CT for COVID-19 (not shown). A, CTPA shows a large saddle embolus in bilateral main pulmonary arteries. B, Initial pulmonary arteriography shows filling defects in the right lobar arteries and corresponding abnormal perfusion, predominantly involving the right upper lobe (arrow) and right middle lobe (asterisk). C, 5-French Cragg-McNamara infusion catheters positioning within the right and left main pulmonary arteries. D, Completion pulmonary arteriography shows a reduction in thrombus burden and improved lung perfusion, particularly in the upper and middle lobes. Also noted are areas of persistent diminished perfusion in the lower lobe compatible with subsegmental emboli. Postintervention, the patient had a decrease in mean pulmonary arterial pressure consistent with hemodynamic improvement. However, shortly afterward, comfort care was provided due to progressive clinical deterioration due to extensive comorbidities and an unfavourable prognosis duration of staff exposure and conserve personal protective equipment (PPE) compared to multisession thrombolysis. Pulmonary artery pressure monitoring in the ICU with catheter removal after improvement may eliminate the need for multiple sessions and follow-up angiography. Patient positioning during catheter-directed thrombolysis may present challenges concerning rapid changes in ventilation requirements and positioning in critically ill COVID-19 patients. Furthermore, thrombocytopenia is common in COVID-19, and the administration of thrombolytic agents in this setting increases bleeding risk and can itself worsen the hematologic profile. 82 Mechanical thrombectomy is also favoured over catheter tPA thrombolysis for patients requiring extracorporeal membrane (ECMO) oxygenation due to the increased bleeding risk associated with ECMO. 84 However, the use of smaller catheters for thrombolysis allows access through alternatives sites, such as the popliteal vein, which may be necessary for COVID-19 patients requiring prone positioning for optimal ventilation ( Figure 5 ).

Appropriate staff education regarding infection control measures and the centralisation of PPE will help ensure workers are equipped to care for the surge of COVID-19 patients safely. 85 85, 87, 88 Modifications in portable chest radiographic techniques, such as acquiring images through a glass window from the hallway outside the patient room, may be necessary. 89 Equipment covers for US machines and probes should be utilised, followed by proper cleaning. 73 Improved indoor air circulation is important for limiting the spread of viral particles and may include the use of high-efficiency particulate air filters. [85] [86] [87] [88] After imaging, approximately 30 min to 1 h should be allowed for room decontamination and passive air exchange.

The American College of Radiology (ACR) provides guidelines regarding the safe resumption of routine radiology care. Overall, the risks of healthcare-acquired COVID-19 must be weighed against the risks of delaying radiology care. Additional safety measurements include screening all patients, workers, and visitors for COVID-19 symptoms; enacting social distancing measures such as limiting the number of patients in waiting rooms with modified scheduling; and creating flags in the electronic medical record with current or recent or suspected COVID-19 illness. The ACR recommends a four-tiered approach for the safe resumption of nonurgent radiology care. 90 The Centers for Disease Control and Prevention (CDC) continually updates safety recommendations for healthcare providers and facilities on their website. Some of these recommendations include implementing telehealth, universal use of PPE, and targeted SARS-CoV-2 testing. 91 Unfortunately, no one-size-fits-all approaches and strict adherence to local and institutional policies aligned with CDC guidelines may further minimise the infection rate in the work environment. 88 

This work did not receive any internal or external sources of funding.

The authors do not have any conflict of interest to declare.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

https://orcid.org/0000-0001-8574-3775

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