key: cord-0688878-au4ngk7k
authors: Pontone, Gianluca; Scafuri, Stefano; Mancini, Maria Elisabetta; Agalbato, Cecilia; Guglielmo, Marco; Baggiano, Andrea; Muscogiuri, Giuseppe; Fusini, Laura; Andreini, Daniele; Mushtaq, Saima; Conte, Edoardo; Annoni, Andrea; Formenti, Alberto; Gennari, Antonio Giulio; Guaricci, Andrea I.; Rabbat, Mark R.; Pompilio, Giulio; Pepi, Mauro; Rossi, Alexia
title: Role of Computed Tomography in COVID-19
date: 2020-09-04
journal: J Cardiovasc Comput Tomogr
DOI: 10.1016/j.jcct.2020.08.013
sha: 6b7115acc86ab4f504929a3b76f59293f41dc869
doc_id: 688878
cord_uid: au4ngk7k

Coronavirus disease 2019 (COVID-19) has become a rapid worldwide pandemic. While COVID-19 primarily manifests as an interstitial pneumonia and severe acute respiratory distress syndrome, severe involvement of other organs has been documented. In this article, we will review the role of non-contrast chest computed tomography in the diagnosis, follow-up and prognosis of patients affected by COVID-19 pneumonia with a detailed description of the imaging findings that may be encountered. Given that patients with COVID-19 may also suffer from coagulopathy, we will discuss the role of CT pulmonary angiography in the detection of acute pulmonary embolism. Finally, we will describe more advanced applications of CT in the differential diagnosis of myocardial injury with an emphasis on ruling out acute coronary syndrome and myocarditis.

Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first diagnosis was confirmed in China in December 2019, COVID-19 has rapidly spread worldwide and ravaged the globe. Although COVID-19 is primarily a respiratory disease with involvement of lung parenchyma, several reports have documented that severe forms are associated with a pro-inflammatory cytokine storm leading to systemic inflammation and sepsis with consequent involvement of various other organs, including the cardiovascular system. 1 In this scenario, an integrated Computed Tomography (CT) approach can give valuable information on diagnosis, follow-up and prognosis of patients with COVID-19.

In this manuscript, we aim to provide an up to date assessment of cardiothoracic CT applications of COVID-19 through illustrative clinical cases. We will start with a comprehensive review of the role of CT in the evaluation of COVID-19 pneumonia and pulmonary embolism. We will then present an analysis of advanced cardiac CT applications for early risk stratification of severe forms of the disease, through the quantification of coronary artery calcium score, and the differential diagnosis between chest pain coronary artery disease related versus non-ischemic myocardial injury J o u r n a l P r e -p r o o f 6

In February 2020, Huang et al. 2 published the first report describing the use of non-contrast chest CT in 41 patients with confirmed COVID-19. Since then, the scientific evidence on COVID-19 has been rapidly growing and the clinical indications for chest CT are continuously evolving. Although reverse transcription polymerase chain reaction (RT-PCR) is the required laboratory test to confirm the diagnosis of COVID-19, non-contrast chest CT may represent a valid tool in the initial assessment of this patient population. Nevertheless, currently there is no consensus on its role within the major Professional Scientific Societies. For example, in China, during the early phase of the outbreak, CT was widely used as a supporting tool in the diagnosis of COVID-19. 3 Clinical case 1: A 52-year old male was admitted due to fever and diarrhea. He reported direct contacts with COVID-19 patients. Frontal chest X-ray demonstrated subtle, bilateral opacities involving mainly the mid and lower zones of the lungs and suggested interstitial inflammatory involvement. No pleural effusions were detected. (Figure 1 -panel a) . Because of the local J o u r n a l P r e -p r o o f 7 coronavirus epidemic outbreak, a nasopharyngeal swab was obtained confirming SARS-Cov-2 positivity. On the same day, non-contrast chest CT scan was performed documenting the presence of multiple ground glass opacities (GGO) mixed with inter-lobular and intra-lobular thickening in a "crazy-paving" pattern ( Figure 1 -panels b and c) . The patient was treated with lopinavir/ritonavir and hydroxychloroquine. Four days after admission, his dyspnea worsened dramatically. Follow-up CT showed increased extent of GGOs mixed to new areas of consolidation in the lower pulmonary lobes with a predominant peripheral distribution (Figure 1 -panels d, e, f) . Because of oxygen desaturation, continuous positive airway pressure (CPAP) was initiated. One month after admission, respiratory gas exchanges were improved but he was still febrile. Therefore, an additional CT was performed after the administration of contrast material documenting the presence of a lung abscess containing an air-fluid level in the superior segment of the left upper lobe. GGOs and consolidative areas were significantly decreased compared to the previous CT scan (Figure 1 -panels g, h, i, j, k). No acute pulmonary embolism was detected. Pneumococcal urinary antigen test was positive and he was treated with levofloxacin. After improvement of his clinical condition and two negative RT-PCR results he was discharged. A follow-up CT performed after two weeks showed near complete resolution of the interstitial abnormalities. However, the lung abscess was still present (Figure 1 -panels l, m, n).

The CT findings commonly observed in patients with COVID-19 pneumonia are the expression of acute interstitial lung damage, and resulting parenchymal changes caused by the cytokine storm triggered by the internalization of the virus into the pneumocytes. 7-9 Post-mortem studies have evaluated the histological changes in the lungs of COVID-19 patients, revealing the presence of pulmonary edema, hyaline membranes and alveolar cellular exudates. 10-17 These changes are likely the substrate for the most common CT findings detected such as GGO and focal consolidation. In a J o u r n a l P r e -p r o o f 8 systematic review including 919 patients with a confirmed diagnosis of COVID-19, GGOs have been reported as the earliest abnormalities, with an occurrence rate up to 88%, whereas consolidations have been described in approximately 32% of the patients. 18 While GGOs were documented in both an isolated form and in association with focal areas of consolidations, pure consolidations were a rare finding. 12, 15, 19 The distribution of the parenchymal lesions was commonly bilateral (88%), multilobar (78%) and peripheral (76%), with frequent involvement of the posterior regions of the lungs (80%). 18 Additionally, several other chest CT findings, such as interlobular septal thickening, bronchiectasis, "crazy paving" and halo sign, have been reported with a lower prevalence. 18, 20 By contrast, pleural and pericardial effusions, mediastinal lymphadenopathy and pulmonary nodules have been rarely observed. 18 Interestingly, early CT reports described involvement of the vascular structures of the lungs. Specifically, a dilatation of the sub-segmental pulmonary vessels surrounding the parenchymal abnormalities has been documented 17, 21 as a possible effect of the locally released pro-inflammatory factors. 20 In the study by Bai et al. this finding was significantly more frequent in patients with COVID-19 pneumonia compared to patients with pneumonia due to other causes (59% vs. 22%, respectively). 21

In COVID-19 patients, the evolution of lung abnormalities on chest CT resembles the progression of other forms of acute lung injury due to viral pneumonia, such as the Severe Acute Respiratory visually scored the involvement of each of the five lung lobes as follows: 0, indicating no involvement; 1, less than 5%; 2, 5-25%; 3, 26-49%; 4, 50-75%; and 5, 75-100%. They found that the total CT score progressively increased until 10 days from the onset of symptoms with a median peak score of 6. Similarly 

Patients with COVID-19 pneumonia may present with different disease severity, from mild to critical forms. Since severe cases can progress to ARDS or death, their identification is of paramount importance to promptly initiate the right treatment. With regards to imaging, in severely ill patients, the most common CT finding is consolidation rather than GGO, with an extensive lung involvement characterized by a bilateral and multilobar distribution. 37

Yang et al. 33 evaluated the performance of a semi-quantitative score calculating the extent of lung opacification in 20 pulmonary segments as a surrogate for disease burden. A score of 0, 1, and 2 was attributed to each lung opacity depending if parenchymal opacification involved 0%, less than 50%, or equal or more than 50% of each region (total score: 0-40 points). A threshold of 19.5 was identified to discriminate between severe and mild cases with a sensitivity of 83% and a specificity of 94%. Similarly, Li et al. 38 employed a semi-quantitative score obtained by summing up the values assigned to each pulmonary lobe on the basis of percent involvement. The median CT-score of the patients group with severe disease was significantly higher compared to the group of patients with mild symptoms (10 versus 5, respectively).

In line with clinical reports which identified older males at higher risk of having a more serious Only few studies reported the specificity of CT in the diagnosis of COVID-19, with values ranging between 24% and 94%. 13, 17, 21, 51 There are different reasons that may explain this low specificity.

First, a number of factors influence the performance of RT-PCR, including the site of specimen, the stage of disease, the viral load, and the reliability of the testing kit. 47, 52 The sensitivity of RT-PCR ranged from 60% to 89%, depending on the specimen site (throat sample vs. sputum, respectively). 53 In particular, a lower sensitivity of RT-PCR has been reported in elderly patients, reflecting the possible poor cooperation of the subjects leading to improper sampling. 51 Importantly, in the early phase of the disease, the rate of false negative RT-PCR compared to CT was not negligible. 13, 26, 54 In the study by Ai et al. 13 a sub-group of 258 patients underwent multiple RT-PCR assays. Among the patients in whom RT-PCR turned from negative to positive, 67% showed initial positive chest CT findings.

Second, the CT findings described in the lung parenchyma of patients with COVID-19 are not specific, with a significant overlap with other diseases causing interstitial damage. 25, 55 The differential diagnosis of COVID-19 pneumonia from other forms of viral pneumonia requires a careful evaluation of all clinical information, radiological pattern, and exposure history. [56] [57] [58] [59] In this scenario, the implementation of Artificial Intelligence algorithms into radiologist workflow has shown promising results in improving diagnostic outcomes. 60, 61 Nevertheless, the use of chest CT as a screening test in low disease prevalence regions may lead to a high number of false positive results with further unnecessary downstream diagnostic testing, increased healthcare costs and overload of the healthcare system. 51 Finally, the low interpretation threshold employed by the radiologists for the diagnosis of COVID-19 pneumonia had a positive effect on sensitivity but a negative impact on specificity. 50 The recent introduction of standardized reporting systems ( Table 1) Figure 2 -panels e, f, g, h) . Venous Doppler ultrasound excluded the presence of deep venous thrombosis. He was treated with antiviral therapy and enoxaparin. The final diagnosis was acute PE in addition to early phase COVID-19 pneumonia.

The overall prevalence of acute PE in COVID-19 patients documented by CTPA ranged between 14% and 30%. 74-77 Of note, despite prophylactic or therapeutic anticoagulation, the rate of PE in COVID-19 patients admitted to ICU was in the range of 25-26% supporting a relationship between the severity of the disease and the prothrombotic phenotype of severely ill patients. 78, 79 Interestingly, pulmonary emboli had more frequent segmental distribution (51%) rather than lobar (31%) or central (13%) involvement. 74 A report of the National Institute for Public Health of the Netherlands advises routine D-dimer testing on admission and serially during hospital stay in patients with a proven diagnosis of COVID-19. Instead, CTPA should be reserved to patients with significantly elevated D-dimer on admission (2000-4000μg/ml) or with significant D-dimer increase during the hospital stay. 80 Dual energy CT may be useful for the evaluation of lung perfusion abnormalities in COVID-19 patients not only in the acute setting 81 but also to monitor lung sequelae in follow-up scans.

COVID-19 patients with pre-existing cardiovascular disease seems to be at higher risk of inhospital mortality. 3 Based on the well established association between coronary artery calcium (CAC), as index of subclinical atherosclerosis, and fatal and non-fatal outcomes in patients with stable coronary artery disease (CAD), 82 two preliminary reports 83, 84 have investigated the impact of CAC on the outcome of patients with COVID-19. In both studies CAC was quantified on noncontrast, non-gated chest CT considering that previous investigations demonstrated good agreement with the reference gated CT. 85 Specifically, in a population of 53 patients with proved COVID-19, Fovino et al. 84 demonstrated that a high CAC ≥400 was an independent predictor of in-hospital mortality and intensive care unit admission (odds ratio: 7.86, 95% confidence interval: 1.16-53.01) after adjusting for age and sex. Similarly, Dillinger et al. 83 showed that CAC was significantly associated with first occurrence of mechanical intubation, extracorporeal membrane oxygenation and in-hospital mortality after adjusting for age, sex and traditional cardiovascular risk factors.

Despite these results suggest that CAC might help in the identification of patients who will experience a worse in-hospital prognosis, both studies suffer from similar limitations. First, the use of a composite primary end-point may have introduced a bias due to the competing risk between the endpoints. Second, the value of all potential confounders, especially those related to lung injury, was not evaluated limiting the assessment of CAC as an independent predictor of worse prognosis in this particular population.

In the setting of COVID-19, myocardial injury has been usually defined as an increase of troponin level above the 99 th percentile of the upper reference limit during the course of the disease. 86 Recent data suggested that the prevalence of myocardial injury in COVID-19 patients ranged between 7% and 36%. 2, 65, 66, [87] [88] [89] Of note, patients with elevated cardiac troponin were proved at increased risk of morbidity and mortality compared to patients who did not developed cardiac injury. 89 The causes leading to myocardial injury in COVID-19 are multiple 90 and they can be summarised as follows:

(1) Acute coronary syndrome (ACS) due to either cytokine mediated plaque instability or inflammatory prothrombotic stage; 91 2) Myocardial mismatch between myocardial demand and consumption of oxygen leading to type 2 myocardial infarction; [92] [93] [94] (3) Direct cardiac damage mediated by the membrane protein angiotensin converting enzyme 2; 95 (4) Inflammatory myocarditis due to the massive release of interleukin-1 and interluking-6, occurring in the advanced stage of the disease. 96 Due to this complex scenario and due to the overlapping of clinical presentation, interpretation of elevated troponin may be extremely challenging. 86 Therefore, additional cardiac imaging is often required to clarify the diagnosis, to guide the therapy and to establish the prognosis of these patients (Figure 3 -panel a) . Echocardiography was normal.

Nasopharyngeal swab tested positive for SARS-CoV-2 infection. A CT scan consisting of a noncontrast acquisition followed by an ECG-triggered CCTA was performed. The non-contrast chest CT documented multiple, patchy GGOs in both lungs consisting with viral pneumonia (Figure 3panels b, c, d) . CCTA excluded the presence of pulmonary embolism (Figure 3 -panels e, f) and showed normal coronary arteries (Figure 3 -panels g, h, i) . The final diagnosis was myocardial injury with non-obstructive CAD.

According to the recently published EACVI position paper, 86 the diagnostic work-up of COVID-19 patients with myocardial injury has to be guided by the pre-test probability of CAD based on symptoms, age, sex, cardiovascular risk factor, and previous history of CAD (Central Illustration).

In particular, in patients with high probability of ACS, such as in the presence of ST-elevation myocardial infarction (STEMI) or high-risk non-STEMI, ICA should be considered. On the other hand, CCTA should be reserved to patients at low and intermediate risk of ACS with equivocal presentation where it can replace ICA in ruling-out ACS thanks to its excellent negative predictive value. 100, 101 This may help avoid unnecessary exposure to all members of the cardiac catheterization laboratory, decrease personal protective equipment utilization and limit patient procedural risk. 99 

When myocardial injury is detected in the absence of obstructive CAD, myocarditis should be considered as a possible differential diagnosis. 102 Nowadays, cardiac magnetic resonance (CMR) is considered the imaging modality of choice for diagnosing myocarditis. 103 Typical CMR features of acute viral myocarditis include diffuse myocardial edema on T2-weighted imaging, hyperemia on early gadolinium enhancement imaging, areas of myocardial fibrosis with a non-ischemic distribution on late gadolinium enhancement (LGE), increased signal on native T1 and T2 mapping, 104 and increased extracellular volume (ECV). 105 Interestingly, preliminary studies in which CMR was performed in patients with active COVID-19 or who recovered from COVID-19 showed that the most common finding was myocardial edema (54% to 100%) while fibrosis on

LGE was present in a lower proportion of patients (30% to 41%). These results support the theory of inflammation as the primary mechanism of myocardial injury in patients with COVID-19. [106] [107] [108] Nevertheless, the use of CMR may be limited during a pandemic due to contamination issues of personnel and patients and due to reduced availability related to long environmental cleaning time. 99 In this scenario cardiac CT may represent a valid alternative to CMR, facilitating the differential diagnosis in COVID-19 patients with myocardial injury 109 Figure 4 -panels a, b, c) . CCTA excluded coronary artery disease (Figure 4 -panels d, e, f) and perfusion abnormalities in the myocardium (Figure 4 -panels g, j) . The delayed CT acquisition documented a sub-epicardial area of hyperdensity in the basal, infero-lateral wall of the left ventricle (Figure 4 -panels h, k, i, l) . Imaging was suggestive of myocarditis in addition to earlyprogressive COVID-19 pneumonia.

In myocarditis myocardial fibrosis can occur as focal areas of replacement fibrosis following myocyte death or as diffuse fibrosis due to the expansion of the interstitium surrounding the myocytes. 110 Despite the different molecular structures, iodine contrast material and gadolinium present similar kinetic and ECV distribution. 111 Therefore, imaging of myocardial fibrosis by CT is feasible with good agreement with CMR, as documented in the detection and quantification of acute and chronic myocardial infarction. 111 Specifically, late iodine enhancement (LIE) CT allows the identification of focal fibrosis whereas ECV CT permits the detection of diffuse myocardial injury.

J o u r n a l P r e -p r o o f 21 Currently, only little data is available on the performance of LIE CT in patients with acute myocarditis. 109, 112 Of note, the largest analysis including 20 patients with CMR-proven acute myocarditis was performed with spectral CT. 113 In this proof-of-concept study, LIE spectral CT showed a sensitivity of 100% in the detection of myocardial fibrosis on a per-patient based-analysis compared to LGE CMR. Additional evaluation of pre-contrast and post-contrast CT images allows myocardial ECV assessment. 114 This may be of interest in patients with myocarditis since they usually present higher ECV compared to controls, as demonstrated in a previous CMR study. 115 Also, adding ECV to the diagnostic algorithm may improve the overall accuracy of CT in the diagnosis of myocarditis when focal fibrosis is not present. 115 Although these preliminary results support the role of CT in the evaluation of myocardial damage in patients with suspected myocarditis, further larger studies are warranted before its implementation in the clinical arena.

During SARS-Cov-2 pandemic, CT may be used as a comprehensive, non-invasive imaging modality which allows for the evaluation of lung parenchyma, patency of pulmonary and coronary arteries and myocardial damage. The era of the "quadruple rule-out" has just begun. The score of a single calcified lesion is calculated by multiplying the area of the lesion, which is often acquired automatically, with the density-weighting factor (DWF). The DWF of a lesion derives from the maximal CT attenuation within that calcified lesion, and it is 1 for calcifications with maximum density of 130 to 199 HU, 2 for calcifications with a maximum density of 200 to 299 HU, 3 for calcifications with maximum density of 300 to 399 HU, and 4 for calcifications with maximum density ≥400 HU. The formula for scoring an individual lesion is:

Agatston score (lesion) = Area x DWF 99 All the scores obtained from each individual lesion, irrespective of location or coronary distribution, should be then summed together to determine the total Agatston score:

Agatston score (total) = ∑ Agatston score (lesion) 99

When reporting the Agatston score of a patient, both the score of each coronary vessel (left main, left anterior descending, left circumflex, and right coronary artery) and total score should be specified. 90, 99 Peak attenuation weighting factor 

Acquisition protocol: ECG triggered / gated CT acquired 7-10 minutes after the injection of contrast material

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Clinical features of patients infected with 2019 novel 76

Acute Pulmonary Embolism in Patients with COVID-19 at CT Angiography and Relationship to d-Dimer Levels

Acute Pulmonary Embolism and COVID-19

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

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence

Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands

Pulmonary Vascular Manifestations of COVID-19 Pneumonia

Prognostic Value of Coronary Artery Calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)

on behalf ofCOVID Research Group of Lariboisiere Hospital CAC and C in P with C-19. Coronary Artery Calcification and Complications in Patients with COVID-19

Subclinical coronary artery disease in COVID-19 patients

Validation and prognosis of coronary artery calcium scoring in nontriggered thoracic computed tomography: systematic review and metaanalysis

The role of cardiovascular imaging for myocardial injury in hospitalized COVID-19 patients

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

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

Heart and Lung Multimodality Imaging in COVID-19

Acute Infection and Myocardial Infarction

ST-Segment Elevation in Patients with Covid-19 -A Case Series

Myocardial injury in COVID-19: The role of coronary computed tomography angiography (CTA)

ST-Elevation Myocardial Infarction in Patients With COVID-19: Clinical and Angiographic Outcomes

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection

The European Society for Cardiology. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic

Society of Cardiovascular Computed Tomography guidance for use of cardiac computed tomography amidst the COVID-19 pandemic Endorsed by the American College of Cardiology

COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome

Initial Imaging-Guided Strategy Versus Routine Care in Patients With Non-ST-Segment Elevation Myocardial Infarction

Acute myocardial injury, MINOCA, or myocarditis? Improving characterization of coronavirus-associated myocardial involvement

Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations

Cardiovascular magnetic resonance techniques for tissue characterization after acute myocardial injury

Cardiac Computed Tomography in Troponin-Positive Chest Pain: Sometimes the Answer Lies in the Late Iodine Enhancement or Extracellular Volume Fraction Map

Cardiac Magnetic Resonance Characterization of Myocarditis-Like Acute Cardiac Syndrome in COVID-19

Cardiac Involvement in Patients Recovered From COVID-2019 Identified Using Magnetic Resonance Imaging

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

Evaluation of myocarditis with delayedenhancement computed tomography

Assessment of myocardial fibrosis with cardiovascular magnetic resonance

Characterization of acute and chronic myocardial infarcts by multidetector computed tomography: comparison with contrast-enhanced magnetic resonance

Quadruple Rule-Out" With Computed Tomography in a COVID-19 Patient With Equivocal Acute Coronary Syndrome Presentation

Usefulness of Late Iodine Enhancement on Spectral CT in Acute Myocarditis

Myocardial Extracellular Volume Quantification by Cardiovascular Magnetic Resonance and Computed Tomography

CMR in patients with severe myocarditis: diagnostic value of quantitative tissue markers including extracellular volume imaging