key: cord-334495-7y1la856
authors: Agricola, Eustachio; Beneduce, Alessandro; Esposito, Antonio; Ingallina, Giacomo; Palumbo, Diego; Palmisano, Anna; Ancona, Francesco; Baldetti, Luca; Pagnesi, Matteo; Melisurgo, Giulio; Zangrillo, Alberto; De Cobelli, Francesco
title: Heart and Lung Multimodality Imaging in COVID-19
date: 2020-06-24
journal: JACC Cardiovasc Imaging
DOI: 10.1016/j.jcmg.2020.05.017
sha: 
doc_id: 334495
cord_uid: 7y1la856

Abstract SARS-CoV-2 outbreak has rapidly reached a pandemic proportion and has become a major threaten to global health. Although the predominant clinical feature of COVID-19 is an acute respiratory syndrome of varying severity, ranging from mild symptomatic interstitial pneumonia to acute respiratory distress syndrome, the cardiovascular system can be involved with several facets. As many as 40% hospitalized patients presenting with COVID-19 have pre-existing history of cardiovascular disease and current estimates report a proportion of myocardial injury in COVID-19 patients ranging up to 12%. Multiple pathways have been advocated to explain this finding and the related clinical scenarios, encompassing local and systemic inflammatory response and oxygen supply-demand imbalance. From a clinical point of view, cardiac involvement during COVID-19 may present a wide spectrum of severity ranging from subclinical myocardial injury to well-defined clinical entities (myocarditis, myocardial infarction, pulmonary embolism and heart failure), whose incidence and prognostic implications are currently largely unknown due to a significant lack of imaging data. The use of integrated heart and lung multimodality imaging plays a central role in different clinical settings and is essential in diagnosis, risk stratification and management of COVID-19 patients. Aim of this review is to summarize imaging-oriented pathophysiological mechanisms of lung and cardiac involvement in COVID-19 and to provide a guide for an integrated imaging assessment in these patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak arisen in central China at the end of December 2019 has rapidly reached a pandemic proportion and the associated disease (COVID-19) has become a major threaten to global health (1) . As the pandemic grows, treating physicians are challenged with different and complex clinical scenarios. The most prominent feature of COVID-19 is an acute respiratory syndrome of varying severity, ranging from mild symptomatic interstitial pneumonia to acute respiratory distress syndrome (ARDS). However, several reports have stirred the attention to possible cardiovascular involvement during SARS-CoV-2 infection: as many as 40% hospitalized patients presenting with COVID-19 have pre-existing history of cardiovascular disease and current estimates report a proportion of myocardial injury in COVID-19 patients ranging up to 12% (2) (3) (4) . Identification of myocardial injury is associated to a dismal prognosis independently and on top of coexisting previous cardiovascular diseases, therefore recognition of its underlying mechanisms may offer a therapeutic opportunity (4) . In this context, the use of multiple diagnostic imaging techniques may apply to both heart and lung to provide an integrated assessment of cardiac and pulmonary function and to refine diagnosis, risk stratification and management of COVID-19 patients.

The pathogenesis of COVID-19 is characterized by two distinctive but synergistic mechanisms, the first related to viral replication and the second to host immune response (5) .

The disease primarily involves the lungs and progresses through three stages with increasing severity, corresponding to distinct histopathological, imaging and clinical findings(6-8).

1. The first stage involves incubation period, SARS-CoV-2 replication in the respiratory system and potential spread to target organs. During this phase alveolar and interstitial inflammation is mild, patchy and usually shows bilateral, peripheral and lower distribution, with patients presenting mild respiratory and systemic symptoms.

2. The second stage is characterized by localized lung inflammation, that shows different grades of severity, ranging from severe interstitial inflammation and thickening to air space consolidation. Patients develop symptoms of viral pneumonia and eventually hypoxia, leading to clinical deterioration and need for hospitalization. 3 . In a subgroup of patients transition to the third stage occurs. This phase is dominated by widespread lung inflammation and systemic inflammatory syndrome triggered by dysregulated host immune response and cytokine storm, causing hyperinflammation, ARDS, shock and multi-organ damage.

Clinical features of COVID-19 are variable. While the majority of patients present with only mild respiratory and systemic symptoms, some progress to severe forms of viral pneumonia and eventually develop severe systemic inflammatory manifestations, with an increasingly higher case-fatality rate (7) . Cardiovascular adverse events may occur at different stages complicating the course of the disease and leading to unfavorable outcomes (Central Illustration).

Definition of cardiac involvement in COVID-19 is challenging, as SARS-CoV-2 infection has multifaceted effects. From a clinical point of view, cardiac involvement during COVID-19 may present a wide spectrum of severity ranging from subclinical myocardial injury to well-defined clinical entities. In a comprehensive understanding, the following clinical scenarios may be encountered: a) primary cardiac involvement; b) secondary cardiac involvement; c) worsening of previous cardiovascular diseases ( Table 1) .

Primary cardiac involvement. This may be the consequence of viral tropism for the endothelium and (presumably) for the myocardium. A link between the respiratory syndrome and the pleomorphic cardiovascular manifestations associated with COVID-19 could be identified in the angiotensin converting enzyme 2 (ACE-2), a membrane-bound enzyme that serves as cell-entry receptor for the SARS-CoV-2(9). This receptor is expressed in a variety of tissues, including lung alveolar epithelial cells and enterocytes of the small intestine, as well as arterial smooth muscle cells and endothelial cells (9) . Based on previous data from the SARS-CoV epidemic, myocardial infection by coronavirus is a possibility: in an autopsy series, SARS-CoV RNA was found in 35% sampled hearts, along with macrophage infiltration and myocardial damage (10) . The extent to which these finding may also apply to SARS-CoV-2 is unknown. To date, no cases of SARS-CoV-2 nucleic acid isolation from myocardial specimens have been described. However, several cases reported on the occurrence of severe myocarditis during laboratory-proven COVID-19 (11) (12) (13) (14) (15) . In all these cases myocarditis caused severe left ventricular dysfunction, but showed some degree of systolic function recovery following medical therapy, ranging from progressive improvement to complete myocardial function restoration. A single case of myo-pericarditis complicated by life-threatening cardiac tamponade has been reported, again without direct isolation of SARS-CoV-2 from the drained pericardial fluid (12) . In the absence of proven SARS-CoV-2 viral infection of the myocardium, the clinical picture overlap of these case reports with other possible differential diagnoses calls for prudence in diagnosing SARS-CoV-2 virus-related myocarditis.

Secondary cardiac involvement. This is the result of indirect myocardial damage during SARS-CoV-2 infection. Of note, it may represent the convergence of multiple different mechanisms. In a post-mortem examination from a COVID-19 patient who developed ARDS, interstitial mononuclear inflammatory cells were noted in heart specimens without structural damage (16) . Hyperinflammatory response in advanced stage of the disease elicits a cytokine storm, chiefly mediated by IL-1 and IL-6 pathways closely resembling hemophagocytic lymphohistiocytosis, a life-threatening hematologic disorder characterized by uncontrolled proliferation of activated lymphocytes and macrophages, with massive release of inflammatory cytokines (9) . These cytokines have been implied in myocardial injury and adverse remodeling in clinical and experimental models of acute coronary syndromes (ACS) and may exhibit direct negative inotropic and metabolic effect onto cardiomyocytes in sepsis-like settings (17) . In addition, IL-1 plays a proven role in atherothrombosis and the resulting hyperinflammatory milieu may provoke atherosclerotic plaque instability and a pro-coagulant state with increased risk of arterial and venous acute thrombotic events, including type 1 myocardial infarction (MI) and pulmonary embolism (PE). Indeed, there is raising concern that COVID-19 patients are more prone to develop thromboembolic venous events and disseminated intravascular coagulation (18, 19) .

Secondary cardiac involvement may also be the consequence of hypoxia-induced myocardial damage that could lead to type 2 MI. This condition could either unmask underlaying obstructive coronary artery disease, or present as myocardial infarction with non-obstructive coronary arteries (MINOCA) in case of intense oxygen supply-demand imbalance (20) .

Moreover, altered pulmonary hemodynamics may play a role in secondary cardiac involvement. In severe COVID-19 pneumonia, use of higher positive end-expiratory pressure may be associated with increased right ventricular (RV) afterload and strain due to higher pulmonary arterial pressure and pulmonary vascular resistance. Pulmonary circulation hypoxic vasoconstriction and superimposed pulmonary thromboembolic events may further precipitate these effects.

Worsening of previously existing cardiovascular diseases. This is frequently observed during COVID-19 and may explain the higher prevalence of patients with pre-existing cardiovascular comorbidities in the non-survivor cohorts (3, 4, 21) . Indeed, patients with heart failure (HF) are particularly vulnerable to hemodynamic decompensation during viral infections (22) . Furthermore, in predisposed patients, arrhythmias may ensue as a result of multiple mechanisms, including hypoxia, systemic inflammation and side effects of drugs used in the treatment of COVID-19 (i.e. hydroxychloroquine often combined with azithromycin) (2) .

Chest X-Ray. The recent COVID-19 radiological literature has been molded by the Chinese experience, with the vast majority of reports focusing on the role of chest computed tomography (CT), almost neglecting chest X-ray (CXR) contribution. On the other hand, European hospitals have drawn diagnostic algorithms in which CXR is described as a first line triage tool, mainly due to its availability and feasibility and to long reverse transcription polymerase chain reaction (RT-PCR) turnaround times. Furthermore, the American College of Radiology points out that CT room decontamination after scanning COVID-19 patients may disrupt radiological service availability, and suggests that portable chest CXR might be considered the optimal tool to minimize the risk of cross infection (23) . As recently reported, CXR demonstrates typical radiographic features in the vast majority of COVID-19 patients, including ground-glass opacities and consolidation, while pleural effusion is not common (Table 2 and Figure 1 ). In a retrospective cohort of 64 patients, Wong et al. found that the common CT findings of bilateral involvement, peripheral distribution, and lower zone dominance can also be assessed on CXR and that severity of CXR findings peaked at 10-12 days after symptoms onset, consistently with previous CT reports (24) . Despite the fact that 6 out of 64 patients demonstrated CXR abnormalities before eventually testing positive on RT-PCR, baseline CXR sensitivity resulted 69%, being significantly lower than that reported for initial RT-PCR and baseline CT (25) . Moreover, differently from what has been previously reported about chest CT, radiographic and virologic recovery times were not significantly different, thus reducing the role of CXR in clinical monitoring (25) . A retrospective analysis of 9 South Korean patients who underwent both chest CT and CXR further decreased the sensitivity of CXR imaging in detecting COVID-19 pneumonia to 33.3% (26) . However, the significance of this result is limited by the small sample size. Recently, Bandirali et al.

proposed a role for CXR in asymptomatic or minimally symptomatic patients in epidemic regions, which may have positive radiographic findings even after 14 days of quarantine (27) .

Up to date, there is no consistent report accurately depicting the course of disease on serial CXR images.

Chest Computed Tomography. Chest CT is a highly accurate imaging modality for pneumonia identification and characterization. As recently reported, chest CT demonstrates typical imaging features in COVID-19 patients, including bilateral ground-glass opacities (GGOs), crazy paving pattern (GGOs with superimposed inter/intralobular septal thickening) and/or consolidations, predominantly in subpleural locations in the lower lobes; typically, discrete pulmonary nodules, lung cavitation, pleural effusion and lymphadenopathies are not present(28,29)(Table 2 and Figure 2 ). Pan et al. demonstrated that multiple CT scans could accurately depict the course of disease, summarized in 4 CT-based stages (28) . The typical COVID-19 pneumonia often starts as small subpleural GGOs, mainly affecting the lower lobes (early stage, 0-4 days after symptoms' onset), which then rapidly develops into crazy paving pattern and consolidation areas, typically affecting both lungs (progressive stage, 5-8 days after symptoms' onset). Thereafter, dense consolidation become the most frequent finding (peak stage, 9-13 days after symptoms' onset). When infection resolves the consolidation areas are gradually absorbed with residual GGOs and subpleural fibrotic parenchymal bands (absorption stage, >2 weeks after symptoms' onset) (Figure 2) . Ai et al.

found that with RT-PCR as a reference, the sensitivity of chest CT imaging for COVID-19 is 97% (25) . Interestingly, these radiological findings are also observed in patients with clinical symptoms but negative RT-PCR results and that almost 50% and 33% of these patients have been respectively reconsidered as highly likely cases and as probable cases by a comprehensive evaluation (25) . Furthermore, 60% to 93% of patients had initial positive chest CT consistent with COVID-19 before the initial positive RT-PCR results (25) . Finally, 42% of patients showed improvement of follow-up chest CT scans before the RT-PCR results turning negative (25) . Nevertheless, it is worth emphasizing that patients with RT-PCR confirmed COVID-19 infection might have normal chest CT findings at admission, when disease is still subtle (30) . Additionally, chest CT can be used for characterization of COVID-19 pneumonia severity. Yang et al. proposed a CT-based severity score defined by summing up individual scores from 20 lung regions: the individual scores in each lung, as well as the global severity score, were found to be higher in severe COVID-19 when compared with mild cases (sensitivity: 83.3%, specificity: 94%)(31).

for lung evaluation presenting features that make it very attractive for assessment of patients affected by COVID-19 (32) (33) (34) . LUS can be performed with any two dimensional scanner, including portable ones, using linear, convex or phase array probes. Specifically, highfrequency linear probe is recommended to assess the pleural line, phase array low-frequency probe is suggested to evaluate deep consolidation, while micro convex probe with small footprint is useful for evaluating posterior fields in supine patients. The entire chest can be scanned with the probe oriented longitudinally or obliquely along the intercostal spaces. The scanning protocol consists in 12-zone examination with 6 regions per hemithorax: upper and lower parts of anterior, lateral, and posterior chest wall demarcated by the anterior and posterior axillary line (32, 33) . COVID-19 pneumonia is characterized by initial interstitial damage with a bilateral, peripheral and posterior distribution followed by parenchymal involvement (34) . LUS effectively detects the areas affected by subpleural interstitial syndrome with the appearance of B-lines, which increase in number as the pathology spreads up covering most of the pleural line. These findings correspond to GGOs and reticular pattern at CT scan ( Table 2) .

The characteristics of the B-lines help to distinguish within interstitial syndrome between pneumonia or ARDS and cardiogenic pulmonary edema. Specifically, inflammatory patterns are characterized by the presence of bilateral, irregularly distributed B-lines with spared areas and coalescent B-lines mostly in posterior fields; furthermore, the pleural line appears typically thickened and irregular with reduced or absent lung sliding (32) . As the disease progresses, lung consolidations become frequent. The subpleural consolidation areas are identified as anechoic hemispheric areas close to the pleural line with a hyperechogenic base.

Extensive consolidation appears as non-translobar and translobar consolidation with hepatization of lung tissue and air bronchogram which distinguish them from consolidations in resorptive atelectasis (Figure 3) . However, LUS also presents limits since it is operator dependent and abnormalities affecting the central regions surrounded by aerated lung are not detectable. With the aim of increasing the reproducibility it would be convenient to establish a scanning model and a severity score. The LUS score, validated with the chest CT comparison, provides a numerical assessment of regional loss of aeration that can be used to assess the response to treatments(33) (Figure 3 ).

Echocardiography. Even though echocardiography should not routinely be performed in patients with COVID-19 and restricted to those in whom it is likely to result in a change in management, bedside echocardiography is a clinically useful tool in different clinical settings in Emergency Department (ED), Intensive Care Unit (ICU) and non-ICU wards (35) . Compact and highly mobile machines should be the ideal ultrasound system to adopt, privileging dedicated probes and machines in infected areas. A miniaturized handheld ultrasound equipment that can be easily protected and cleaned may be an alternative option (35, 36) .

A pragmatic strategy based on the use of focused cardiac ultrasound (FoCUS) seems the most reasonable approach (37) . FoCUS should be combined with LUS for the evaluation of patients with respiratory failure. The COVID-19 crisis highlights the need for imagers to be cross-trained (LUS and FoCUS) and be more nimble: sonographers, cardiologists, and emergency physicians who are not familiar with LUS can learn quickly with initial support of expert colleagues and web resources (38) . However, since FoCUS is not being performed as the definitive diagnostic test, if no usable information is obtained, comprehensive echocardiogram and/or other diagnostic testing have to be considered (37) . The aim of echocardiography is to reliably identify cardiac abnormalities and coexisting heart disease in order to facilitate triage and guide patient management. Echocardiography is also recommended for the evaluation of patients who develop symptoms consistent with a cardiac etiology. Information must quickly include biventricular function, gross valvular abnormalities, wall motion abnormalities, pericardial effusions and surrogates of a patient's volume status, including inferior vena cava collapsibility and ventricular size (37) .

Transthoracic echocardiography (TTE) is the standard technique, while transoesophageal echocardiography (TOE) should be avoided due to the high risk of equipment and personnel contamination, unless there is a clearly defined indication that requires TOE imaging or inadequate TTE imaging quality due to patient-specific factors (intubated patients, poor image quality, inability to position the critically ill patient for optimal image acquisition) (35) .

The most common echocardiographic abnormalities encountered in our experience on COVID-19 patients in the non-ICU setting are reported in Table 3 . Acute worsening of respiratory symptoms is a leading indication for performing echocardiography in these patients, frequently depicting a picture of acute cor pulmonale: RV dilatation, paradoxical septal motion and pulmonary hypertension. In this clinical setting PE seems relatively frequent (Figure 4) . Echocardiography may expedite diagnosis of this condition. CT coronary angiography is a well-established tool to effectively and safely rule-out CAD in the setting of acute chest pain, thanks to its excellent negative predictive value (95-100%) (39) . Of note, CT angiography can combine coronary arteries, pulmonary arteries and thoracic aorta assessment using dedicated "triple rule-out" (TRO) protocols. In selected patients with variable degrees of respiratory symptoms, showing cardiac enzyme and Ddimer elevation, a dedicated TRO approach, with lung parenchyma instead of thoracic aorta as the third focus of the examination, may solve different clinical questions in one sitting (40) .

Although most of the currently available CT scanners allow to image coronary arteries with high-resolution and limited motion artifacts, clinical judgement is advised, since dedicated scanners can improve image quality. Additionally, CT angiography could rule-out left atrial appendage thrombus, allowing direct-current cardioversion in patients with atrial fibrillation, thereby limiting operator exposure deriving from TOE examination. Moreover, cardiac CT could provide advanced diagnostic assessment through myocardial characterization (41) .

Indeed, CT examination can be completed with a delayed iodine-enhanced scan to identify areas of myocardial necrosis or fibrosis. This further evaluation may result especially useful in patients with MINOCA, allowing to differentiate myocardial infarction from stresscardiomyopathy, which is typically characterized by absence of myocardial late enhancement, and to diagnose acute myocarditis, detecting myocardial scar with typical nonischemic pattern. In this case, one can speak of "quadruple rule-out" having a single examination looking for lung involvement, coronary and pulmonary artery patency and myocardial scar (42) . However, cardiac CT remains limited in the detection of myocardial edema, which represents the hallmark of acute myocardial inflammation (41) .

Cardiac magnetic resonance (CMR) is the imaging of choice for the diagnosis of acute myocarditis, revealing with high sensitivity focal or diffuse myocardial edema through shorttau inversion recovery (STIR) sequences and mapping techniques (T2 and Native-T1), potentially associated to necrotic foci visible with late gadolinium enhancement (LGE), diffuse expansion of extracellular volume fraction (ECV) and hyperemia (43, 44) (Figure 5) .

The recent introduction of parametric mapping enables CMR to reveal diffuse myocardial edema that can be missed by conventional sequences, increasing its accuracy in the diagnosis of inflammatory cardiomyopathies. Currently, few case reports showed CMR findings consistent with acute myocarditis in patients with laboratory-proven SARS-CoV-2 infection (13) (14) (15) . Myocardial edema was the key for CMR diagnosis in all of these cases, underscoring the importance of including mapping techniques in CMR protocols adopted in COVID-19 patients with suspected myocarditis (43) . Therefore, in selected COVID-19

patients not requiring ICU, when clinical presentation and biomarker alterations suggest acute-onset myocardial inflammation, if the diagnosis is likely to impact on management, CMR may be considered to confirm acute myocarditis, after exclusion of alternative relevant clinical conditions, including ACS and HF, by means of other rapidly available imaging modalities (i.e. cardiac CT scan or TTE).

Nuclear Cardiology Imaging. Nuclear cardiology encompasses several non-invasive imaging modalities and techniques that can be used for myocardial perfusion and viability assessment, as well as for the diagnosis of infective endocarditis, cardiac sarcoidosis and amyloidosis. However, most of these conditions can be proficiently and safely evaluated with other imaging modalities after COVID-19 clinical resolution. Therefore, in COVID-19 patients, the use of nuclear cardiology tests should be restricted to very specific indications when they may yield diagnosis or directly influence the clinical management and no alternative imaging modalities can be performed (i.e. suspected infective endocarditis of prosthetic valves or intracardiac devices), in order to reduce healthcare personnel exposure related to long protocols and imaging acquisition times (45) .

Invasive Cardiac Imaging. When evaluating the role of invasive cardiac imaging modalities in COVID-19 patients, several aspects deserve consideration. In the complex rearrangement of the healthcare service, all the efforts should be directed to ensure the standard-of-care and timely access to the catheterization laboratory for patients with acute cardiovascular conditions, irrespectively of SARS-CoV-2 infection. Therefore, the use of ICA in COVID-19 patients should be restricted to those presenting with clinical or hemodynamic instability, including acute myocardial infarction, myocarditis, cardiogenic shock or cardiac arrest (Figure 6 ). In these cases an invasive strategy is pivotal to ensure diagnosis and interventional treatment (46) . In addition, ICA eventually combined with coronary intravascular imaging or left ventriculography plays an important role in identification and differential diagnosis of MINOCA (9) . Basing on our direct experience, MINOCA accounts for >25% of ACS in COVID-19 patients. Notwithstanding, patient status, severity of respiratory compromise, comorbidities and the risk of futility should be carefully evaluated when considering indication to invasive strategies in COVID-19 patients.

Some clinical and laboratory risk factors for in-hospital death have already been identified in COVID-19 patients (7, 8) . The quantification of lung and cardiac involvement by multimodality imaging could effectively delineate the severity of the disease and eventually the prognosis, providing a base for further clinical decision making.

Quantification of lung damage using a chest CT severity score (CT-SS) has been proposed to identify patients who need hospital admission (31) . This score was defined summing up individual scores from 20 lung regions: scores of 0, 1, and 2 were respectively assigned if parenchymal opacification involved 0%, <50%, or ≥50% of each region (CT-SS range 0-40). The individual scores for each lung as well as the total score resulted significantly higher in patients with clinically severe COVID-19 as compared to mild cases.

A CT-SS <19.5 was highly effective in severe COVID-19 pneumonia rule-out, with a NPV of 96.3%(31).

In the same way LUS could be effective in evaluating COVID-19 pneumonia severity and monitor its modifications over time. For this purpose the numerical assessment of regional loss of aeration measured by global LUS score could represent a useful tool (33) . The global LUS score can be calculated as the sum of regional aeration scores attributed to each lung region during a standard 12-zone examination scanning: 0 if A-lines or <3 B-lines are visualized; 1 if ≥3 B-lines involving ≤50% of the pleura; 2 if B-lines becoming coalescent or involving >50% of the pleura; 3 if tissue-like pattern(33) (Figure 3) . The global LUS score showed good correlation with lung density as assessed by CT scan and has been applied in the ICU setting to quantify and monitor lung aeration in weaning from mechanical ventilation and in ARDS patients on extracorporeal membrane oxygenation (ECMO) (33) . So far, the implementation of the global LUS score to monitor disease evolution and to guide decision making in COVID-19 patients has not been systematically investigated.

Similarly, despite growing evidence pointing at the negative prognostic impact of cardiovascular involvement in COVID-19, no specific risk scores have been developed and validated. Interestingly, although great emphasis has been posed on the link between myocardial injury and mortality, the actual incidence of specific cardiovascular clinical conditions (myocarditis, MI, PE and HF) and the respective prognostic implications in different stages of COVID-19 is largely unknown due to a significant lack of imaging data (4) . A systematic approach with the use of multimodality imaging to precisely characterize COVID-19-related cardiovascular manifestations should be warranted to provide clinicians with comprehensive risk stratification tools.

The imaging modalities are useful in the management of COVID-19 patients in different clinical settings, from triage in the ED to ICU and non-ICU wards (Figure 7) . Emergency Department/Triage. A rapid and efficient diagnosis of COVID-19 is of paramount importance to accurately manage the high number of patients presenting to the ED with suspected SARS-CoV-2 infection. Considering the high probability of COVID-19 among patients currently accessing ED with fever and respiratory symptoms, the main goal is to stratify patients with positive SARS-CoV-2 RT-PCR test (or with clinically highly suspected infection despite a negative test) in order to discharge those with mild symptoms and admit to non-ICU or ICU Departments those with severe or life-threatening infection. A simultaneous clinical evaluation and LUS performed by the same visiting physician (reducing the number of operators exposed), combined with laboratory testing and CXR, allow a fast diagnosis, risk stratification and decision-making regarding patient destination. In this context, LUS has the potential to rapidly discriminate initial forms of COVID-19 from advanced presentations (34) . FoCUS is an adjunct to recognize specific ultrasound signs in patients with or suspected cardiac symptoms (37) . This quick stratification could be subsequently confirmed by CXR, trying to limit the number of CT scans performed in the ED setting, reserving CT for cases with uncertain diagnosis or to rule-out other causes of illness such as PE. Of note, several patients have a severe form at ED presentation, rapidly becoming non-invasive ventilation (NIV)-dependent and, therefore, cannot easily undergo CT scan; in these patients, LUS is of paramount importance for rapid diagnosis and stratification. Despite its potential diagnostic utility, no unequivocal advantage has been demonstrated for a LUS-guided strategy over standard CXR and (if appropriate) CT scan evaluation in patients with suspected or confirmed COVID-19. Furthermore, LUS requires closer contact with the patient, potentially exposing clinicians to higher risk of aerosolized particles inhalation, mandates use of more protective personal protection equipment (PPE) and should be performed by trained personnel. In this context, LUS application is a promising technique, although its role should not be overemphasized in the absence of solid evidence; on the contrary, CXR and clinical evaluation remain pivotal for initial patient assessment.

Beyond ED evaluation, an important approach to take care of patients and prevent transmission is the application of telemedicine (47) . Telemedicine/e-visits could be combined with home triage for patients reporting worsening symptoms or self-monitored parameters, the latter being ideally performed by dedicated teams providing both clinical evaluation and LUS at the patient's home, thus more accurately differentiating patients who could continue remote monitoring and medical therapy at home from those who need hospitalization.

COVID-19 Departments is currently based on supportive care (i.e. oxygen therapy, NIV if necessary) and a combination of empirically prescribed drugs (i.e. hydroxychloroquine, antibiotics, antivirals, glucocorticoids or anti-cytokine therapies). Along with clinical and laboratory evaluation, imaging is fundamental to assess COVID-19 evolution and response to therapy, both in daily clinical activity and in the context of controlled pharmacological/interventional trials. Baseline CT scan is frequently used to confirm diagnosis and to obtain detailed information on disease extension and severity, thus becoming also a reference for subsequent imaging follow-up (28) . Of note, considering its known advantages (portability, bed-side evaluation, safety), LUS seems particularly useful for serial assessments during hospital stay and may be useful to determine timing of CT imaging (34) .

Alongside with lung imaging, FoCUS could be useful to assess volume status and concomitant cardiac involvement, reserving cardiac CT, ICA and CMR only for selected cases, including suspected concomitant MI, PE or myocarditis (37) .

ICU represents the most challenging setting in the management of COVID-19 patients. Ideally, a baseline CT scan is needed in all critically ill patients requiring ICU admission, in order to precisely describe morphological lung involvement. As in the previously described clinical settings, serial LUS and CXR are fundamental to monitor disease evolution in ICU patients, while CT scan could be used when clinical changes are observed, substantial modifications in morphological lung damage are suspected, or ventilator-related complications need to be excluded (32) . Echocardiography could be useful to rule out concomitant cardiogenic causes of respiratory manifestations (37) . Furthermore, FoCUS allows a non-invasive hemodynamic monitoring in the ICU setting: assessment of biventricular function, estimated stroke volume, filling pressures, pulmonary pressures, and central venous pressure (37) . Similarly, TTE helps in identifying patients at high risk of ventilator weaning failure and guides tailored therapeutic strategy. Finally, when mechanical respiratory and circulation support with ECMO is needed, both TTE and TOE are important to guide device selection (veno-venous vs. veno-arterial) based on concomitant cardiogenic cause, assist during device placement (cannulation), and monitor cardiac function and devicerelated complications during support (48) .

negative RT-PCR test deserve special consideration. As medical systems are overwhelmed, accurate balance between infection prevention and adequate healthcare assistance delivery should be pursued. Beside clinical disease probability assessment, while serology tests are under development, current strategies to reduce in-hospital SARS-CoV-2 spread from asymptomatic patients rely on RT-PCR nasopharyngeal swab test, with important limitations (49) . Therefore, adherence to international guidelines recommendations, and restriction of imaging tests to those really impacting on patients' clinical management are advocated (35, 36) . Triaging protocols should differentiate between patients requiring nondeferrable but schedulable imaging examinations, who can be appropriately managed after RT-PCR test result is available, and those with urgent or emergent acute cardiovascular conditions, who should be considered SARS-CoV-2 positive until proven otherwise.

Optimization of healthcare network and patient pathways is required to avoid contamination between infected individuals and SARS-CoV-2 negative patients, while maintaining adequate health assistance. Both patients and healthcare workers should be provided with standard PPE and keep social distance when possible. Basing on our experience, RT-PCR test should be performed according to local resources in selected patients requiring hospitalization or undergoing aerosol-generating high-risk procedures, after body temperature measurement and a clinical triaging questionnaire evaluating history of fever, dyspnea or cough and SARS-CoV-2 exposure in the last weeks (50) .

Current COVID-19 pandemic, sharply increased the examination workload of the Imaging Departments. The in-hospital infection rate was about 41% in one of Chinese experience: 29% hospital staff and 12.3% inpatients (2) . In Italy, up to 9% of overall cases were reported among healthcare workers with an estimated in-hospital infection rate of 10.8% (51) . SARS-CoV-2 transmission occurs through direct inhalation of droplets but also by touching eyes, nose or mouth after hand contact with contaminated surfaces. Imagers, nurses and technicians are at high risk especially due to the close patient contact performing imaging studies. In order to prevent and mitigate the transmission, preventive measures must be implemented encompassing facilities, imaging equipment, PPE and machine disinfection procedures (35) .

Specific in-hospital routes between imaging Department and COVID-19 wards should be defined. The special environment for COVID-19 dedicated imaging should include a contaminated equipment area, a separated report room and a staff cleaning room. The use of mobile equipment and dedicated scanners, ultrasound probes and machines for infected patients should be encouraged (35) .

Staff must undergo rigorous nosocomial infection training and equipped with highquality PPE ( Table 4) , balancing the risk of transmission with the potential for scarcity of PPE, considering in some cases their re-using, with adequate precautions. The use of a checklist and a step-by-step process to ensure proper wearing (donning) and removing (doffing) are recommended. Imaging personnel not directly involved should avoid any contact, and the distance between the technician and patients must be, preferably, >1-2 meters. All patients should wear a surgical mask during imaging. Left-lateral patient positioning with the scanner on the right side of the bench may ensure the longest distance between patient's face and the echocardiographer during TTE examination. Personnel involved in TOE examinations should wear full PPE as this procedure is aerosol-generating.

While cuffed endotracheal tube and close-circuit ventilation could reduce the risk of aerosol generation in intubated patients, NIV carries a higher risk of droplets spreading. The level of protection during TOE should be full both in ICU or non-ICU context (35) .

As SARS-CoV-2 is sensitive to most standard viricidal disinfectant solutions, imaging machines should be thoroughly cleaned. It is recommended to use soft cloth dipped in 2000 mg/L chlorine-containing disinfectant or 75% ethanol for scanners disinfection (35) .

Generally, for echocardiographic probes it is advised to immerse them for ≤1 hour without using hot steam, cold gas, or abrasive agents, as ethylene-oxide or glutaraldehyde-based methods. Automated disinfection solutions should be available. Air, object surfaces and floor disinfection in the COVID-19 dedicated Imaging Department should be carried out according to the daily operation specifications. In reading rooms social distancing should be remembered and all non-essential items removed (35) .

As of today, none of the healthcare workers in the cardiac imaging Department of our Hospital, have been infected with SARS-CoV-2, underscoring the relevance of adequate PPE use and adherence to a rigorous safety protocol (52) . Since PPE availability could be a significant issue especially in hard-hit areas, the use of clinical judgement should be emphasized to avoid additional staff exposure deriving from performing imaging tests unlikely to yield clinically important information on COVID-19 positive or suspected positive patients. Thus, the need for procedures requiring stringent PPE (i.e. TOE or nuclear imaging) and the possibility to perform alternative imaging modalities (i.e. cardiac CT) or no procedure at all should be thoroughly assessed in order to optimize PPE use.

SARS-CoV-2 outbreak has rapidly reached a pandemic proportion and has become a major threaten to global health. Although the predominant clinical feature of COVID-19 is an acute respiratory syndrome of varying severity, the cardiovascular system can be involved with several facets. Heart and lung multimodality imaging plays a central role in different clinical settings and is essential in diagnosis, risk stratification and management of COVID-19 patients. In order to prevent and mitigate the transmission, key preventive measures must be adopted encompassing the equipment, the facilities, the healthcare personnel and the disinfection procedures. 61-year-old woman with SARS-CoV-2 positive RT-PCR swab test presenting with sudden severe dyspnoea associated with significant D-dimer increase: CT pulmonary angiography shows gross filling defect in right pulmonary artery lobar branch for right upper lobe (A); lung parenchyma windowing demonstrates bilateral, subpleural GGOs and consolidation areas, typical for COVID-19 pneumonia (B); TTE shows RV dilatation and septal shifting, indirect signs of severe pulmonary hypertension (C-D). 58-year-old woman with SARS-CoV-2 positive RT-PCR swab test presenting after 1 week of fever (38.5 °C), cough, diarrhea with recent onset of typical chest pain, elevated cardiac markers (hs-TnT 222 ng/L), ST-segment depression in inferior and lateral leads at ECG, and inferior septum hypokinesia at TTE. Triple rule-out CT shows peripheral lung opacities (A-B) characterized by crazy paving pattern involving both the inferior lobes, with posterior distribution, suggestive for COVID-19 interstitial pneumonia (boxes), and demonstrates absence of pulmonary embolism (C) or coronary disease (D). CMR shows slight diffuse myocardial hyperintensity on T2 STIR image (E) consistent with a slight increase of T2 relaxation time on T2 mapping: mean value of 55 ms (normal value ≤ 50 ms) with a peak of 61 ms in the inferior septum (G); IR images do not show significant LGE foci. Viral replication and host immune response synergistically determine COVID-19 pathogenesis. As the disease progresses through its three stages, different chest imaging modalities (LUS, CXR and CT) demonstrate worsening lung involvement. In case of severe pneumonia TTE can identify increasing pulmonary hypertension and RV impairment. Cardiovascular complications related to viral infection or to systemic inflammation can occur at different stages of the disease, increasing the risk of adverse outcome, and require specific multimodality imaging assessment. 

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