First reported in Wuhan province of China in December 2019, the novel Coronavirus 2019 (COVID-19), also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread worldwide leading to a substantial public health crisis. The worst affected countries are the USA, Brazil, and India, the total number of cases in the world being over 167 million as of May 24, 2021.1 Common COVID-19 symptoms are fever, cough, dyspnea, myalgia, fatigue, and anosmia. As the pandemic has progressed, abdominal symptoms like loss of appetite, nausea, vomiting, diarrhea, and abdominal pain have also been noted1. An early study reported that approximately 81% of patients of COVID-19 had mild symptoms, 14% had severe disease, including pneumonia and dyspnea, and 5% had critical illness including multiorgan failure and respiratory failure.2 It has been reported that COVID-19 disease predisposes to a prothrombotic state marked by elevated D-dimer and thrombocytopenia, potentially resulting in thromboembolic complications. In addition, an immune-mediated cytokine storm in the second week of this viral illness may set into motion severe complications like ARDS and multiorgan disease, which may be fatal. The gold standard for the diagnosis of COVID-19 is real time polymerase chain reaction (RT-PCR) on nasopharyngeal and/or oropharyngeal swab; however, its sensitivity is reported to be only 30-60 % due to limitations of sample collection, transportation, and kit performance.3 Radiography is insensitive in identifying early disease but has a valuable role in the follow-up and prognostication of diagnosed patients. Typical chest CT findings of COVID-19 pneumonia are peripheral, multifocal GGO, and consolidative opacities.
Chen et al4 reported 12 of 33 COVID patients testing negative on RT-PCR initially, showing CT features of COVID-19 disease and being confirmed on subsequent repeat RT-PCR. A study by Meng et al5 described abnormal CT findings in 58 asymptomatic COVID-19 patients at presentation, although 16 of them later developed symptoms. COVID-19 infection is increasingly being described as a multiorgan disease rather than just viral pneumonia. There have been numerous reports of the disease causing thromboembolic, gastrointestinal, renal, cardiovascular, and neurologic complications. Prior literature has focused chiefly on imaging of pneumonia with CT and radiography. In this review, we wish to describe the imaging manifestations of COVID-19 disease in the various organ systems of the human body.
Pathogenesis of COVID-19
The inhaled virus SARS-CoV-2 binds to the epithelial cells of the nasal cavity and starts multiplying, following which it enters alveolar epithelial cells in the lung by binding to angiotensin-converting enzyme 2 (ACE-2) receptors. Cell entry is via binding of the spike protein of SARS-CoV-2 virus to the ACE-2 receptor.5 ACE-2 receptor is expressed in various sites apart from the lung epithelium, including cardiovascular endothelium, small bowel, liver, biliary epithelial cells, pancreatic islet cells, kidney, and brain, making these organs prone to injury. It has been postulated that receptor expression may potentiate cytotoxic effects by aiding local viral infection and replication.
Due to the destruction of cells expressing ACE-2, there is relative ACE-2 deficiency leading to derangement of Renin-Angiotensin system, elevated Angiotensin-II, and reduced Angiotensin1-7, which potentiates endothelial inflammation, thrombosis, and hypertension.6 This may also play a role in multiorgan injury to the heart, kidney, and liver.
COVID-19 is recognized as a multisystem disease due to its affinity for ACE-2 receptor and cytokine-mediated inflammation. Early investigations suggest that the most common laboratory findings are elevated D-dimer levels, mild thrombocytopenia, and PT prolongation, which are associated with increased mortality.6,7 Decreased lymphocyte count due to direct cytotoxic action, leukocytosis, and neutrophilia due to hyperinflammatory response is also seen in COVID-19 patients.7 Patients with COVID-19 show an increased risk of vascular thrombosis, manifesting as deep vein thrombosis, pulmonary embolism, arterial stroke, and visceral or peripheral artery thrombosis. Above hemostatic abnormalities are primarily related to an inflammatory syndrome characterized by elevated cytokines, including IL-1 and IL-6, referred to as thromboinflammation.8 The various system involvement is described below with its imaging features.
The most common neurologic symptoms reported in COVID-19 are headache, altered consciousness, pathologic wakefulness after sedation, agitation, and confusion. Jain et al.7 and Mahammedi et al.9reported that the most common positive neuroimaging studies revealed stroke and the former described that finding of either large ischemic or hemorrhagic stroke was associated with high mortality Figure 1 and Figure 3 Chougar et al.10 found several cerebrovascular complications such as ischemic stroke, microhemorrhages, deep vein thrombosis, cytotoxic lesions of corpus callosum, multifocal white matter enhancing lesions, and basal ganglia abnormalities in COVID-19 patients.
Kandemirli et al.11 found increased cortical signal on FLAIR (Fluid-attenuated inversion recovery), cortical diffusion restriction, cortical blooming, leptomeningeal enhancement, and subcortical and deep white matter abnormality. Radmanesh et al.12 described 2 patterns of MRI findings, one being deep and subcortical white matter hyperintensity with mild diffusion restriction and the other one being diffuse subcortical and callosal microhemorrhages Figure 2. Kremer et al.13 described mainly 3 patterns of MRI findings after excluding ischemic infarcts-medial temporal lobe hyperintensity, non–confluent white matter hyperintensities with diffusion restriction with or without enhancement with or without microhemorrhages and isolated widespread microhemorrhages.
The various proposed mechanisms for neurologic implications include the following – Direct central nervous system spread, and neurotropism is supported by evidence of earlier SARS-CoV strains gaining access to the CNS via olfactory pathways or the bloodstream and known to cause meningitis and encephalitis.14 Another proposed etiology is indirect neurologic involvement due to an excessive systemic proinflammatory response, which may cause widespread dysregulation of homeostasis with coagulopathy and increase the risk of acute cerebrovascular diseases.
COVID-19 may also lead to parainfectious autoimmune-based neurologic complications such as acute disseminated encephalomyelitis (ADEM) and Guillain Barré syndromes, which are recognized complications of microbial infections.15,16 Lastly, since most patients were admitted to ICUs forARDS, more general assumptions may also be considered, such as delayed post-hypoxic leukoencephalopathy, metabolic or toxic encephalopathy, and posterior reversible encephalopathy syndrome (PRES).17,18 Various patterns of neurologic abnormalities in COVID-19 patients are summarized in Table 1.
TABLE 1. Neurologic complications of COVID-19 infection.
|Complications and MRI manifestations||Proposed etiology|
|1||Cerebrovascular complications including ischemic, hemorrhagic stroke and deep vein thrombosis||Virus associated coagulopathy|
|2||Basal ganglia abnormalities||Immune-mediated|
|3||Cytotoxic lesion of the corpus callosum||Inflammatory response to COVID-1975|
|4||FLAIR hyperintensity in medial temporal lobes||Neuroinvasion 76|
|5||Multifocal bilateral non-confluent white matter hyperintensities +/-diffusion restriction+/- enhancement+/- hemorrhage.|
|6||Isolated bilateral microhemorrhages||Disseminated intravascular coagulation(DIC), hypoxia or small vessel vasculitis|
|7||Cortical FLAIR hyperintensity with diffusion restriction+/- cortical blooming +/-leptomeningeal enhancement11||Neurotropism, cytokine storm, hypoxia|
|8||Diffuse confluent white matter hyperintensity||Delayed post hypoxic leukoencephalopathy or post-infectious demyelination|
|9||Acute necrotizing hemorrhagic encephalopathy 77|
The case report revealed bilateral thalamic, medial temporal, and subinsular regions with hemorrhagic change & rim enhancement.
|Breach in the blood-brain barrier due to cytokine storm rather than demyelination. 78|
Common clinical symptoms of COVID19 pneumonia include fever, cough, and expectoration, while few present with vomiting, dyspnea, and low oxygen saturation levels.19 Fleishner society recommends imaging in symptomatic COVID-19 patients with worsening respiratory status or those with moderate and/or severe disease. Imaging is not recommended in asymptomatic and/or mild patients or for primary diagnosis or screening of patients.20 Chest radiographs were found to be insensitive in diagnosing COVID-19 pneumonia; however, findings of multifocal haziness and consolidations have been described.21 With the progression of pneumonia, consolidations may become more confluent with an ARDS type diffuse involvement in later stages (Fig 4).
Point of care ultrasound is a useful diagnostic and prognostic tool for COVID-19, particularly in ICU and isolation wards.22 Lung ultrasound findings in COVID-19 include thickened pleural lines(shred sign), vertically oriented echogenic B lines, multifocal consolidations with air bronchograms, and A-lines during the recovery phase.23,24
Literature of COVID-19 pneumonia has been focused on chest CT due to its high sensitivity to diagnose lung abnormalities. Tao et al. 3 described a high sensitivity of CT to diagnose COVID-19 with RT-PCR as the gold standard. They also found positive CT findings in 75 % of patients in a group of 413 suspected COVID patients with a negative RT-PCR. Similar findings were reported by Korkmaz et al.25 This underscores the need to utilize CT as a problem-solving tool in the present scenario. CT findings of COVID-19 have been described as multifocal bilateral GGO and/or mixed GGO- consolidation with rounded morphology and bilateral, multifocal, peripheral, and lower lobe distribution.26,27 (Fig 5) Other common features of interlobular septal thickening, air bronchogram, and vascular enlargement and less common findings of reverse halo, nodule with halo, subpleural line sign, subpleural transparent line sign, fibrotic streaks, bronchiectasis, and bronchus deformation were also described. (Fig 6A-B). A variant of reverse halo sign – bull’s eye sign has been described in COVID-19, which consists of a central ground-glass nodule surrounded by an inner ring of air and an outer ring of ground glass. These likely represent areas of organizing pneumonia.28 Pleural effusion, pericardial effusion, lymphadenopathy, cavitation, and pneumothorax are uncommon findings that may be seen on disease progression.29,30
Temporal follow-up of CT findings has revealed initial unifocal GGO followed by an increase in number and size of GGO, progressing to mixed GGO-consolidation with or without crazy paving pattern reaching a peak around ten day’s, thereafter showing slow resolution with linear subpleural consolidative opacities or reverse halo sign which is typical to organizing pneumonia (Fig 7).29,31 Pulmonary fibrosis may develop with time, which manifests as mild to severe subpleural and peribronchovascular fibrosis, macrocystic lung changes, and bronchiectasis. CT helps evaluate post-COVID fibrosis, especially in those patients who present with persistent cough and dyspnea (Fig 6C-F).32,33
Vascular and perfusion abnormalities, including dilatation, tortuosity of pulmonary vessels not limited to the area of GGO, mosaic perfusion, focal oligemia, and focal hyperemia have been identified in CT images of COVID-19 patients. The typical response to pneumonia is hypoxic vasoconstriction in the consolidated lung. In COVID-19, there is inflammation-mediated paradoxical vascular dilatation in the consolidated lung. This leads to shunting of blood to poorly ventilated areas of lung parenchyma, which further exacerbates hypoxia due to ventilation-perfusion mismatch.34
The various pulmonary findings of COVID-19 are summarized in Table 2.
TABLE 2. Pulmonary complications of COVID-19 infection.
|Complication and imaging manifestations||Proposed etiology|
Round ground-glass opacity, consolidation in multifocal peripheral distribution
Common features of interlobular septal thickening, air bronchogram
Uncommon features of reverse halo, nodule with halo
|Progressive pulmonary infiltration|
Organizing pneumonia pattern
|3||Vascular enlargement||Increased blood supply due to inflammation|
Mild to severe subpleural and peribronchovascular fibrosis, macrocystic lung changes, bronchiectasis.
Affects lung in previously involved sites.
Severe cases, diffuse lung involvement with potential candidate for lung transplant.
|Residual fibrosis after resorption of pneumonitis|
Various reports of coagulopathy and acute pulmonary embolism (PE) have been published in recent times, indicating a higher risk of thromboembolic events in COVID-19 pneumonia. An elevated risk of developing PE was associated with these factors- obesity, elevated D-dimer, elevated CRP, and rising D-dimer values over time (Fig 8).35
In a study comprising 100 COVID-19 patients, a 23% prevalence of acute pulmonary thromboembolism was found.36 Another study showed that patients with COVID-19 infection undergoing lower extremity CT angiography (CTA) had a higher propensity for lower extremity clots when compared to the controls.37 A study on 81 critically ill patients found the incidence of venous thromboembolism (VTE) to be 25%.38
COVID-19 predisposes to arterial and venous thrombosis, the imaging features of which are not specific and appear similar to those associated with other diseases (Fig 9). However, if radiologists are familiar with its prevalence and pathogenesis in these patients, it can aid in early detection and a more favorable outcome. Since these patients undergo aggressive anticoagulation therapy, there is a possibility of increased incidence of bleeding complications which can be diagnosed on imaging.
COVID-19 can affect the cardiovascular system through direct and indirect mechanisms, such as myocardial injury, acute coronary syndromes (ACS), right ventricular dysfunction and/or acute cor pulmonale, arrhythmias, and cardiogenic shock.39 There have been reports of clinically diagnosed myocarditis with supplemental imaging findings.40,41 Figures 10 and 11 Abnormalities of the cardiac rhythm including new-onset atrial fibrillation, sinus node dysfunction, complete heart block, and ventricular arrhythmias have also been described.19
Puntmann et al.42 found contrast-enhanced MRI (CEMRI) evidence of cardiovascular involvement and myocardial inflammation in 78 % and 60% respectively of recently recovered COVID-19 patients without any relation to severity and course of acute illness or preexisting conditions. The CEMRI abnormalities detected were elevated native T1, elevated native T2, delayed myocardial enhancement, and pericardial enhancement.42
A multitude of factors has been recognized in the pathophysiology of cardiovascular manifestation. ACE-2 receptor is widely present in the cardiovascular tissue – in cardiac myocytes, fibroblasts, and endothelial cells, suggesting a role in a direct viral injury mechanism.43,44 It has been proposed that patients who have preexisting cardiovascular disease have increased ACE-2 levels, predisposing them to complications.45,46 Myocarditis has been suggested as an acute cause of cardiac dysfunction, and it has been postulated that the viral load correlates with the severity of myocardial injury. Another mechanism is cytokine storm or systemic inflammatory response syndrome, which can cause myocardial injury due to demand ischemia.47 Troponin levels are often raised primarily in severe cases and are associated with poor prognosis. Increased pulmonary vascular pressure occurring secondary to ARDS and pulmonary thromboembolism can cause right ventricular dysfunction.48 While various viral infections are a risk factor for myocardial infarction (MI),49 the risk is higher with COVID-19, which could be related to the increased coagulability causing an increase in thrombotically mediated MI.
The various cardiovascular complications of COVID-19 are summarized in Table 3.
TABLE 3. Cardiovascular complications of COVID-19 infection.
|Complications and imaging manifestations||Proposed etiology|
|1||Acute pulmonary embolism, venous thromboembolism, Arterial thrombosis —role of CTPA and CT Angiography||Increased coagulability|
|2||Acute coronary syndromes||Increased coagulability|
|3||Cardiomyopathy||Direct myocardial injury or immune-mediated reaction|
|4||Acute cor pulmonale||Secondary to ARDS and increased pulmonary vascular pressure, Pulmonary thromboembolism|
|5||Arrhythmia||Hypoxic state due to ARDS or myocarditis|
|6||Cardiogenic shock||Myocarditis and/or myocardial infarction|
Myocardial edema and delayed enhancement on CE-MRI
|Direct injury (myocardial inflammation) or cytokine storm|
|8||MIS-C related myocarditis|
Multisystem Inflammatory Syndrome in Children (MIS-C)
Multisystem inflammatory syndrome in children (MIS-C was first described as a Kawasaki-like syndrome in patients with a history of prior contact with a COVID-19 patient. It has been proposed that MIS-C is the result of a post infectious phenomenon due to abnormal IgG antibody mediated enhancement of the disease. An alternative hypothesis suggests that coronaviruses due to their known ability to block interferon responses can result in a delayed cytokine storm leading to MIS-C.50
Case series and studies have described a broad spectrum of multisystem imaging findings in this syndrome, including perihilar bronchial wall thickening, perihilar or lower lobe consolidations, rapid development of pulmonary edema, ARDS, pulmonary embolism, cardiomegaly, coronary aneurysms, pericardial effusion, gall bladder wall thickening, splenic infarcts, echogenic kidneys, right iliac fossa bowel thickening, and mesenteric lymphadenopathy.51,52 MIS-C related myocarditis imaging findings have been described on echocardiography to show transient systolic dysfunction and on cardiac MRI to show myocardial edema without enhancement.53
GIT and Hepatobiliary Involvement
Tian et al19 reported the most common gastrointestinal symptoms to be anorexia and diarrhea in adults and children respectively. Other gastrointestinal symptoms in COVID-19 patients included nausea, vomiting, gastrointestinal bleeding, and abdominal pain. A multicenter study by Pan et al.54 reported that over 18% of COVID-positive patients presented with abdominal symptoms, and approximately 5% had isolated gastrointestinal symptoms without respiratory complaints.
Studies have reported findings of COVID-19 pneumonia in lung bases on abdominal imaging for non–respiratory clinical complaints, most commonly abdominal pain. This emphasizes that radiologists must pay attention to lung bases, especially during this pandemic, for early diagnosis, even when not clinically suspected.55,56
It was reported in a recent study that 57% of acutely ill COVID positive patients were found to have positive findings on abdominopelvic CT, most common of which were small bowel thickening, solid organ infarctions, and vascular thrombosis Figure 12A-D).57
Other related findings of bowel wall hyper-enhancement, pneumatosis, portal venous gas, and fluid-filled colon have been described in literature. On surgery and histopathology, some of these have correlated with yellow discoloration of bowel, ischemic bowel, and fibrin thrombi within the necrotic bowel.58,59
ACE-2 receptors are found throughout the gastrointestinal tract, with the most significant functional role in the small bowel and colon. SARS-CoV-2 binding to bowel epithelial cells leads to mucosal inflammation (e.g., enteritis). Viral load causes alterations in intestinal microbial flora and cellular regulation of fluid and electrolytes, leading to diarrhea. There have been few case reports of COVID-19 patients presenting with abdominal pain, being diagnosed with epiploic appendagitis. Possible etiology of this condition is inflammation and venous thrombosis, both known associations of COVID-1960,61 (Fig 12E-F).
Almost 40% of COVID-positive patients have abnormal liver function tests (LFT) on admission, and LFT abnormalities are associated with higher fevers, higher levels of C-reactive protein, and longer hospital stay.62 Liver dysfunction is likely secondary to the virus’s binding to hepatic ACE-2 receptors causing an immune cytokine storm, leading to hepatocellular inflammation and damage of hepatocytes. The imaging correlate of liver dysfunction is hepatic steatosis which has been described on ultrasound in COVID-19 patients. A study has demonstrated that COVID19 patients with high body mass index and non–alcoholic fatty liver disease (NAFLD) has a greater risk for both progression in liver damage and COVID-19. Progression of liver damage in chronic liver diseases in the setting of COVID-19 may be complicated by hepatic failure, hepatic encephalopathy, and gastrointestinal bleeding to diagnose which imaging would be helpful.63
An upper abdominal ultrasound-based study on 37 COVID-19 positive patients showed gallbladder sludge in 60%, wall thickening in 3%, and pericholecystic fluid in 3% patients.59 Another study showed gallbladder distension and wall edema in 25% of COVID-19 patients reported as possible or definite cholecystitis (Fig 13A-D).57 SARS-CoV-2 binding to gallbladder epithelial cells leads to mucosal inflammation and hyperemia. Gallbladder wall edema is also a common finding in acute hepatitis and is an independent predictor of a more severe clinical course.45 Gallbladder wall edema seen in COVID-19 may reflect hepatocellular damage, either directly by SARS-CoV-2 or by a reactive inflammatory response.
A study showed that 9 out of 72 patients presented with abdominal pain, tested positive for COVID-19, and showed findings similar to acute pancreatitis.64 Liu et al.65 reported high ACE-2 expression in pancreas, which lead to 2% and 17% evidence of pancreatic injury in non–severe and severe patients, respectively (Figure 13 E,F). The various abdominal findings of COVID-19 are summarized in Table 4.
TABLE 4. Abdominal Involvement of COVID-19 infection.
|Complication and imaging manifestations||Proposed etiology|
|1||Small bowel thickening, solid organ infarctions and vascular thrombosis||SARS-CoV-2 binding to bowel epithelial cells leads to mucosal inflammation, prothrombotic state|
|2||Fluid-filled bowel loops identified on CT were consistent with the clinical diarrhea||Alterations in intestinal microbial flora and cellular regulation of fluid and electrolytes|
|3||Liver dysfunction and hepatocytes- USG altered echotexture, steatosis||Binding of virus to hepatic ACE-2 receptors or immune cytokine storm|
|4||Gallbladder sludge in 60%, wall thickening in 3% and pericholecystic fluid||Viral binding to ACE-2 or secondary to hepatocyte damage|
|5||Acute pancreatitis||Inflammation due to viral binding of ACE-2 receptor|
|6||Epiploic appendagitis||Inflammation and venous thrombosis|
There is significant co-expression of ACE-2 and Transmembrane protease, serine (TMPRSS) in cells of proximal convoluted tubules, which places them at high risk of injury due to SARS-CoV-2.66 Cytokine storm may also have a role in renal injury. A review by Zaim et al. described that 0.5%-19% of COVID-19 patients may show varying degrees of renal injury. Possible renal manifestations of COVID-19 include acute kidney injury, electrolyte abnormalities, proteinuria, and hematuria.67 Imaging-wise, this may be seen on ultrasound as increased renal cortical echogenicity and altered corticomedullary differentiation. This knowledge is relevant for radiologists as they must exercise caution while advising contrast-enhanced CT, which may be replaced by ultrasonography or non–contrast MRI.
Myalgia, arthralgia and fatigue have been commonly reported symptoms in COVID-19.68 During the SARS-CoV-1 epidemic, late complications including reduced bone mineral density (BMD), osteoporosis, and osteonecrosis were reported related to prolonged ICU stay, corticosteroid use, systemic inflammation, and prothrombotic state. Similar complications may be anticipated during the current SARS-CoV-2 pandemic.69 There have been case reports of myositis and rhabdomyolysis related to COVID-19 effects. MRI findings of myositis include swelling, T2 hyperintensity, and enhancement within the muscles. Myonecrosis is identified by the stipple sign showing foci of enhancement in a rim enhancing area of non–enhancement.70
Post-infectious neuropathies have also been rarely reported in COVID-19, and their imaging findings include nerve enlargement, hypoechogenicity, loss of architecture, and T2 hyperintensity on ultrasound and MRI, respectively.70,71 Soft tissue hematomas may develop in COVID-19 due to virus-induced bleeding complications or anticoagulation prophylaxis of thrombotic coagulopathy.72 Arthritis in COVID-19 may be viral related or more commonly due to the triggering of chronic rheumatologic diseases such as Rheumatoid or Psoriatic arthritis. Viral induced arthritis shows non–specific findings of synovial enhancement and thickening on MRI, while inflammatory arthritis may reveal polyarticular arthritis and erosions.70,73,74
The novel Coronavirus brought the whole world to a standstill in 2020. Being a new disease, its clinical manifestations, radiological imaging, and treatment have rapidly evolved owing to ongoing research. It has been realized that the effects of COVID-19 are not limited to the lung and involve several organ systems in the body. The role of imaging is ancillary to the RTPCR test for diagnosis but indispensable for prognosticating and following up COVID-19 pneumonia. Imaging is also imperative in diagnosing thromboembolism, complications in brain, cardiovascular system, gastrointestinal, and hepatobiliary system.
Fuente: Current Problems in Diagnostic Radiology 00 (2021) 1-14 https://doi.org/10.1067/j.cpradiol.2021.06.015
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