Diagnostic value: The gold standard for the diagnosis of SARS-CoV-2 is the real-time reverse transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal samples. Although it has excellent specificity, sensitivity may vary between 42%-83%[18,19]. This wide range in reported sensitivities can be attributed to inadequate or improper tissue sampling, early timing of sampling (when the viral load is low), or laboratory errors. High false-negative rates can have a crucial impact, as patients who are misdiagnosed as negative can continue transmitting the virus within the hospital or the community. Moreover, the initial RT-PCR test kits had long processing times and were not readily available in certain regions due to high demand.
Given the need for rapid triaging of patients and prevention of transmission, chest CT was proposed as a rapid, reproducible and widely available screening tool[21-23]. However, many methodologic concerns and shortcomings are present in studies reporting on the performance of chest CT as a diagnostic tool. The majority of published studies based their findings on populations with high disease prevalence or with only symptomatic patients, introducing a selection bias. Furthermore, some studies used CT as a binary test with a low threshold for determining a positive examination, which may also overestimate sensitivity and compromise specificity[26,27]. Several meta-analyses have attempted to generate an estimated sensitivity; however, many of them did not assess the risk of bias in the included studies.
As a result of these discrepancies, there is great variability in the reported sensitivities (60%-98%) and specificities (25%-53%) of chest CT in the detection of COVID-19 pneumonia . A Cochrane meta-analysis including data from 31 studies with low risk of bias and 8014 participants, 53% of which were COVID-19 positive, showed that chest CT has 89.9% sensitivity and 61.1% specificity. The use of CT as a screening tool has multiple limitations, including high cost, radiation exposure, and transmission risk within the radiology department due to clustering of patients. It has poor specificity due to overlap with other pulmonary diseases (i.e., viral pneumonias, pulmonary edema, interstitial lung disease), and therefore cannot be used as a confirmatory test. Moreover, with a reported negative predictive value of 42%, CT chest can lead to false negative results in patients early in the course of the disease. In view of these limitations, the World Health Organization (WHO), the American College of Radiology (ACR) and other societies have released statements urging against the use of chest CT as a screening tool[32,33].
Indications: Chest CT is a valuable imaging modality that can provide an accurate assessment of the severity and extent of disease, detect complications, evaluate treatment efficacy and rule out alternative diagnoses.
Based on the guidelines released by the Fleischner Society, chest imaging is indicated in patients with worsening clinical status and for rapid triage of patients with moderate-severe respiratory symptoms in a setting of high pre-test probability and low RT-PCR availability. Additionally, the WHO recommends chest imaging when RT-PCR is negative but clinical suspicion for COVID-19 remains high, and to help guide admission to the medical floor vs intensive care unit (ICU) in patients with moderate-severe illness. Although imaging is not indicated in suspected cases with mild symptoms based on the Fleischner Society guidelines, the WHO recommends chest imaging in suspected or confirmed mild cases to help decide on hospital admission vs discharge, especially in patients at high risk of disease progression. Neither of the aforementioned guidelines clarify which chest imaging modality needs to be used on each clinical scenario or provide guidance on follow-up imaging intervals and scanning protocols.
Imaging findings: COVID-19 pneumonia causes a wide spectrum of acute lung injury ranging from mild inflammation to diffuse alveolar damage. Ground-glass opacities (GGOs) are the most common imaging manifestation, seen in 65% of patients. GGOs are bilateral in 88%, although they may remain unilateral throughout the course of the disease in 17% of cases[38,39]. They typically have a peripheral/ subpleural distribution with a predilection for the posterior segments of the lower lobes, but may be diffuse in 29% of cases. GGOs may be pure (more commonly) or be accompanied by consolidations (mixed pattern). Intralobular and interlobular septal thickening, likely a combination of interstitial inflammation and fluid, is seen in 27% of cases. Superimposed GGOs giving a crazy-paving pattern is seen in 12% and may be a sign of more severe lung injury and disease progression. Consolidations, seen in up to 32% of cases, have a subpleural or peribronchovascular distribution and may or may not have air-bronchograms[37,40]. They are associated with more severe disease requiring management in the ICU. Cavitations are not typically seen.
Subsegmental vascular enlargement (greater than 3 mm) within parenchymal abnormalities has been described in up to 64%-89% of patients[42,43]. Although the exact pathogenesis is uncertain, it is thought to be related to hyperemia or thrombotic microangiopathy[43,44]. Pulmonary nodules are considered atypical, as they are seen in only 9% of cases. The halo sign (consolidation surrounded by GGO) and the reverse halo sign (GGO surrounded by a rim of consolidation) have been described late in the disease course of COVID-19 pneumonia but are considered non-specific. Pleural thickening has been described more commonly than pleural effusions (1.6%). Mediastinal adenopathy is rarely seen in COVID-19 pneumonia (0.7%) and when seen it should point to another process such as concurrent chronic congestive heart failure or even bacterial superinfection. The presence of pericardial effusion should raise concern for COVID-19 related cardiac injury.
Differential diagnosis: GGOs are a non-specific finding that may occur in numerous other entities. However, the distribution and pattern of GGOs as well as accompanying features can aid in the differential diagnosis. Pulmonary edema can manifest with GGOs in a central distribution and peripheral sparing, along with smooth interlobular septal thickening, peribronchial cuffing, cardiomegaly, dilated pulmonary veins, and pleural effusions. Diffuse alveolar hemorrhage is characterized by diffuse peribronchovascular GGOs but no subpleural predominance. Drug-induced pneumonitis can present as non-specific interstitial pneumonia with subpleural sparing. E-cigarette vaping induce lung injury (EVALI) can present with peribronchovascular GGOs with subpleural sparing. Bronchiolitis is characterized by centrilobular opacities, as well as bronchial wall thickening, bronchiectasis and air-trapping[45,46].
Pulmonary manifestations of SARS-CoV-2 on CT overlap with other viral infections. In SARS-CoV-1 and MERS infection, GGOs are typically unifocal and less extensive, and the halo and reverse halo signs are atypical[47,48]. Influenza can also manifest as bilateral GGOs, with or without consolidations, with a lower lobe predilection; bronchiectasis and pleural effusions are, however, more common. In parainfluenza, centrilobular nodules and bronchial wall thickening are typical. Respiratory syncytial virus infection is characterized by centrilobular nodules (tree-in-bud) and asymmetric consolidations. In adenovirus infection, bilateral multifocal GGOs and consolidations are seen in a lobar or segmental distribution, frequently with pleural effusion[46,50].
Lobar bacterial pneumonia (primarily caused by Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma) manifests as lobar or multilobar consolidations, typically with regional adenopathy and pleural effusions. Bronchopneumonia (Staphylococus aureus, Pseudomonas, Klebsiella, Haemophilus influenzae) manifests as confluent peribronchial consolidations, GGOs, centrilobular nodules, bronchial wall thickening, and mucoid impaction. Lymphadenopathy, pleural effusions and cavitations are common with some of these organisms. Interstitial pneumonia (caused by Mycoplasma and other atypical agents) presents with patchy GGOs, consolidations and centrilobular nodules.
Structured reporting: The Fleischner society recommends RT-PCR in patients with CT findings suggestive of COVID-19. The Radiological Society of North America (RSNA) suggested the use of a structured reporting system to decrease reporting variability among radiologists and to reduce uncertainty about the findings that should raise concern for COVID-19. It has been validated by several studies and appears to be useful in clinical decision making[18,51]. According to this system, findings on CT are categorized in 4 categories: typical, indeterminate, atypical and negative for COVID-19 pneumonia.
Typical findings are the bilateral multifocal peripheral GGOs, which may or may not be accompanied by consolidations and thickened interlobular septa. Additionally, typical findings include signs of organizing pneumonia (OP), such as the reverse halo sign. When applied to chest CTs of 211 patients positive for SARS-CoV-2 and 249 negative patients in Italy, the “typical” pattern had a 71.6% sensitivity, 91.6% specificity and 87.8% PPV for COVID-19 infection, although the PPV varied by disease prevalence. In negative patients with a typical pattern (8.4%), the final diagnosis was viral pneumonia other than COVID-19 (81.0%), bacterial infection (9.5%) and drug toxicity (9.5%).
The “indeterminate” category includes findings with a lower specificity for COVID-19 pneumonia. These include GGOs that are non-peripheral, multifocal, diffuse, perihilar, unilateral, with or without consolidations. The “indeterminate” category imposes a diagnostic challenge as there is marked overlap with other infectious and non-infectious diagnoses, such as acute hypersensitivity pneumonitis, Pneumocystis infection and diffuse alveolar hemorrhage.
Atypical findings include lobar or segmental consolidations without GGOs, cavitations, small discrete centrilobular nodules, smooth interlobar septal thickening and pleural effusions. These findings are uncommonly reported in association with COVID-19 pneumonia, and are associated with bacterial pneumonia, necrotizing pneumonia, or aspiration, among others. The “negative” category includes cases with no evidence of pneumonia on CT. The atypical and negative patterns were more frequently observed in SARS-CoV-19 - negative patients.
Similar to other reporting and data systems widely used primarily for cancer reporting, the COVID-19 Reporting and Data System (CO-RADS) was designed by the Dutch Radiological Society to provide a standardized assessment of the level of suspicion for COVID-19 on chest CT. Seven categories were created, with a considerable overlap with the RSNA reporting system: CO-RADS 0 (technical limitations, uninterpretable), CO-RADS 1 (negative or very low suspicion), CO-RADS 2 (low suspicion), CO-RADS 3 (equivocal), CO-RADS 4 (high suspicion), CO-RADS 5 (very high suspicion) and CO-RADS 6 (confirmed by RT-PCR). The pilot study that assessed the performance of CO-RADS included 105 suspected COVID-19 cases, 51% of which were confirmed by a positive RT-PCR. Highest interobserver agreement was seen with the CO-RADS 1 and 5 categories. Performance, however, was tested in a setting of high prevalence of SARS-CoV-2 and low prevalence of other viral pneumonias, which may overestimate the positive predictive value. Further studies have investigated the utility of CO-RADS in larger samples. A study included 859 suspected cases (42% of which were positive by RT-PCR), as well as 1138 controls who presented to the emergency room for other reasons within the same time period (5% of which were incidentally found to be COVID-19 positive). In the symptomatic cohort, when CO-RADS 4 was used as a threshold, sensitivity and specificity were 85% and 85% respectively, whereas for CO-RADS 5 rates were 78% and 93%, respectively. In asymptomatic patients, a threshold of CO-RADS 3 had a very poor sensitivity (45%) but high specificity (89%), suggesting that incidental CO-RADS 3 findings should prompt RT-PCR testing. The high sensitivity of CO-RADS 4 and 5 suggests that patients who belong to these categories and have a negative initial RT-PCR need to remain in isolation until a repeat RT-PCR is negative, quarantine has lapsed or an alternate diagnosis is made[29,54].
Various severity scoring systems have been created in order to provide a quantified assessment of pulmonary involvement on chest CT. They usually divide each lung into segments and assign a score for the extent of involvement and nature of opacities. A final score is created by summing the scores for each individual segment. Higher CT severity scores are seen in patients with critical disease compared to those with milder disease and have been associated with worse long-term outcomes. No association has been found between the extent of CT findings and infectivity.
Disease phases: The findings on chest CT follow the temporal changes of COVID-19 pneumonia. Chest CT has a limited value during the first 48 h from symptom onset, as up to 56% of patients have no lung abnormalities[54,57]. Within 4 d, pure GGOs develop, which may have rounded margins or may outline adjacent secondary pulmonary lobules. In the progressive phase of the disease (5-14 d), the GGOs become more extensive and may coalesce into multifocal consolidations. Septal thickening and crazy-paving are more frequent. Findings reach their peak at day 9-13 after symptom onset[38,58]. In the late or absorption phase (after day 14), there is a gradual clearance of GGOs and consolidations. Signs of fibrosis and parenchymal remodeling may develop, which can manifest as parenchymal bands, subpleural lines, interlobular septal distortion and traction bronchiectasis[39,59].
OP has been described as a pattern of response to acute lung injury caused by SARS-CoV-2, similar to other viral infections such as SARS-CoV-1, MERS and influenza[60,61]. It is histologically characterized by fibrous plugs within the alveoli and respiratory bronchioles. The transformation of GGOs into linear consolidations is typical for OP (Figure 1). Consolidations can be single or diffuse in a peripheral or peribronchial distribution. A reverse halo sign and spontaneous migration of infiltrates are commonly seen. Treatment with corticosteroids shows dramatic improvement, as evidenced by the decreased mortality rates in COVID-19 patients on oxygen or mechanical ventilation (MV) receiving corticosteroids for 10 d in the RECOVERY trial. However, this treatment duration may be insufficient, as longer duration and higher doses are typically needed for OP.
Figure 1 Severe coronavirus disease 2019 pneumonia.
Portable chest X-ray and axial image from a computed tomography of the chest in a 52-yr-old female with a history of morbid obesity who was admitted for acute hypoxic respiratory failure secondary to severe acute respiratory syndrome coronavirus 2. A: Chest X-ray shows low lung volumes with diffuse bilateral alveolar and interstitial opacities; B: Chest computed tomography shows diffuse ground glass opacities anteriorly, typical of acute lung injury. The peribronchial and perilobular opacities posteriorly are typical of acute lung injury that has entered a healing phase. The patient subsequently expired.
ARDS occurs in 31% of hospitalized patients with COVID-19 pneumonia and is the third most common complication following sepsis and respiratory failure. Unlike typical ARDS which occurs within 1 wk based on the Berlin definition, ARDS in COVID-19 pneumonia develops within 8-15 d of disease onset[6,65]. ARDS is a clinical diagnosis encompassing features of non-cardiogenic pulmonary edema, and stems from the disordered vasoregulation in the setting of an acute systemic inflammatory response. Autopsies of COVID-19 patients revealed diffuse alveolar damage, as well as microvascular thrombosis. Although ARDS is a clinical diagnosis, imaging can play a supportive role in diagnosis and monitoring of treatment response. In the early exudative phase, diffuse ground glass opacities and consolidations develop primarily in a posterior/basal distribution (Figure 1B and Figure 2B). Perfusion abnormalities may be seen on dual-energy CT as a result of ventilation/perfusion mismatches. In the late phase, 2 wk following the symptom onset, fibrotic changes may occur.
Figure 2 Barotrauma.
A and B: Coronal (A) and axial (B) images from an unenhanced computed tomography of the chest of a 75-yr-old male with no significant past medical history, who was intubated for acute hypoxic respiratory failure secondary to coronavirus disease 2019 pneumonia. There are ground glass opacities anteriorly, as well as consolidations with air bronchograms posteriorly, a pattern typical for acute respiratory distress syndrome. There is a massive amount of air within the mediastinum resulting from alveolar rupture (Macklin effect). The arrow on image (A) points to interstitial emphysema, surrounding a pulmonary vein. The arrow on image (B) points to nonanatomic air within a pulmonary lobule, which may represent the initial barotrauma event. There is extensive soft tissue emphysema in the lower neck and lateral chest wall, as well as in the extraperitoneal space of the abdominal cavity. Bilateral thoracostomy tubes and a peripherally-inserted central catheter are in place. The patient could not be weaned from ventilation and subsequently expired.
Patients with critical disease are at increased risk for complications. Secondary bacterial or fungal infection occurs in up to 15% of inpatients with COVID-19 pneumonia and is a major cause of mortality. Moreover, an increased incidence of barotrauma events (pneumothorax, pneumomediastinum, pneumopericardium, subcutaneous emphysema) has been observed in COVID-19 patients on MV, particularly in younger age groups (Figure 2). A study showed that 15% ventilated patients with COVID-19 experienced one or more barotrauma events and that the rate was significantly higher compared to ventilated non-COVID-19 patients. Barotrauma was associated with higher mortality rates and longer hospital stay.
Both OP and ARDS have the potential to progress into pulmonary fibrosis (Figures 3 and 4). However, there is a paucity of data with regards to the long-term pulmonary sequela of COVID-19 pneumonia. A study prospectively followed 114 patients who were admitted for severe COVID-19 pneumonia. Follow-up CT scans after 6 mo showed fibrotic changes in 35% of patients. Factors associated with a higher risk of fibrosis were older age (> 50 years), longer hospital stay (> 17 d), ARDS, non-invasive ventilation, tachycardia on admission and high CT severity scores on the initial CT scans. Another study prospectively followed a cohort of 83 patients with no pulmonary or cardiovascular comorbidities, who were admitted for severe COVID-19 pneumonia that was managed without the use of MV. Although there was a temporal improvement in pulmonary function tests and imaging findings in most patients, 33% had impaired diffusing capacity of the lungs for carbon monoxide (DLCO) and 24% had residual lung findings on high-resolution CT 12 mo after discharge, including GGOs in 23%, interlobular septal thickening in 5% and reticular opacities in 4% of patients. Patients with a longer hospital stay, higher peak CT severity scores and those who required high-flow oxygen therapy or non-invasive ventilation were more likely to have residual lung abnormalities on follow-up CT. Studies reporting on long-term outcomes are limited by small sample sizes and lack of histologic correlation. Ongoing trials with larger samples and longer follow-up intervals will help elucidate the long-term outcomes of COVID-19 pneumonia (NCT04483752, NCT04376840, NCT04376840).
Figure 3 Pulmonary fibrosis.
Axial images from computed tomographies of the chest performed 2 yr apart in an 83-yr-old male with a history of silicosis. A: In June 2018, there was mild lung hyperaeration with mild reticulation; B: In August 2020, 4 mo after recovering from coronavirus disease 2019 pneumonia, there is extensive fibrosis, with areas of honeycombing, traction bronchiectasis/bronchiolectasis and architectural distortion.
Figure 4 Non-specific interstitial pneumonia.
Axial image from a computed tomography of the chest in a 59-yr-old female 6 mo after recovering from acute hypoxic respiratory failure secondary to coronavirus disease 2019. Mild fibrosis in a peribronchial distribution and subpleural sparing in the right lower lobe is in keeping with mild fibrotic non-specific interstitial pneumonia. There is also a mosaic pattern caused by obstructive small airways disease (confirmed on expiration views, not shown), with altered perfusion in the lungs.
Pulmonary embolism: SARS-CoV-2 causes prothrombotic endothelial injury leading to thromboembolic phenomena, which are further propagated by hypoxia[10,69]. Pulmonary embolism (PE) is seen in 22%-30% of COVID-19 patients who undergo a CT pulmonary angiogram (CTPA) (Figure 5), a rate that is markedly higher than critically-ill patients without COVID-19[70-72]. In a multicenter study of 1042 COVID-19 patients, PE was found in 5.6%. PE was diagnosed on the day of admission in 47%, and was proximal in 46%, segmental in 41%, and sub-segmental in 14%. Of patients with PE, 42% required ICU management and MV, while 20% of PE patients died. Patients on MV were at higher risk for developing PE, irrespective of the extent of lung abnormalities on chest CT. Other risk factors include severe obesity and African-American decent .
Figure 5 Pulmonary embolism.
A-C: Coronal (A) and axial (B and C) images from a computed tomography angiography of the chest in a 53-year-old female with a history of chronic lymphocytic leukemia and asthma who was admitted for acute hypoxic respiratory failure secondary to coronavirus disease 2019 pneumonia, complicated by pulmonary emboli. A large filling defect is seen in the left pulmonary artery extending into lobar and segmental branches (A and B). Diffuse ground glass opacities are noted on the lungs bilaterally (C).
Patients with COVID-19 may have elevated D-dimer levels even in the absence of PE, due to the prothrombotic state induced by the virus. Higher D-dimers are associated with more severe disease. However, COVID-19 patients with PE have significantly higher CRP and D-dimer levels compared to those without PE. A D-dimer value of 2600 ng/mL has been suggested by some studies as the threshold to prompt suspicion for PE[70,72]. The Dutch National institute of Public Health recommends routine D-dimer testing on admission and serial testing during hospital stay. If initial D-dimers are < 1000 μg/L and a significant increase to > 2000-4000 occurs, imaging for deep venous thrombosis or PE should be pursued.
Apart from the D-dimer trend, other clinical factors that should prompt a CTPA are: worsening hypoxia not explained by the extent of lung involvement, hemoptysis, tachycardia, deep venous thrombosis, and acute deterioration upon mobilization. Presence of kidney disease should not preclude investigation with CTPA, as no significant increase in the risk for acute kidney injury (AKI) has been shown in patients receiving iodinated contrast compared to controls. Dual-energy CT is useful in visualizing perfusion abnormalities, even in the absence of PE. It can demonstrate perfusion defects within lung opacities, and halos of increased perfusion surrounding consolidations, although the significance of these findings has not been determined. The use of pulmonary scintigraphy has been discouraged. Due to the risk of aerosolization with the ventilation component of a V/Q scan, perfusion-only scans have been performed when clinically mandated since the onset of this pandemic, which may lack specificity. Combining Q- SPECT with a low-dose CT has been shown to increase the diagnostic performance of the perfusion scan, achieving higher accuracy than planar V/Q[77,78]. Optical coherence tomography may provide a novel means of assessing for microvascular thrombosis in patients with elevated D-dimer levels and a negative CTPA (NCT04410549).
CT scanning protocols: There is a paucity of guidance regarding the optimal CT techniques and protocols for patients with suspected or proven COVID-19 pneumonia. The Fleischner Society guidelines do not provide recommendations regarding scanning protocols and the need for dose-reduction.
A single-phase, unenhanced chest CT performed with volumetric acquisitions in deep inspiration and a < 3 mm thickness is preferred. Expiratory phase is not considered of value as air trapping has not been associated with the acute phase of COVID-19 pneumonia. Motion artifacts may be present in patients who are short of breath or have cough. Faster scanning by means of faster gantry rotation time and higher pitch can prevent suboptimal imaging. High-resolution CT is not required unless there is concern for interstitial lung disease; it may, however, play a role on follow up to characterize fibrosis.
There is no value in obtaining post-contrast images as the findings of uncomplicated COVID-19 are confined to the lung parenchyma. Contrast-enhanced CT is justified when assessing for complications (e.g., abscess, necrotizing infection) or other diagnoses (such as PE or aortic dissection). If contrast-enhanced imaging is needed, there is no need for pre-contrast imaging.
A study collected data of CT acquisition protocols and dosimetry across 54 healthcare centers worldwide. It demonstrated wide variations in the median volumetric CT Dose index (CTDIvol) and in the median dose length product. It also showed that 30% of COVID-19 patients underwent 2-8 chest CT examinations within one month. Even though the majority of patients affected by COVID-19 pneumonia are adults and the risk for radiation-induced cancer in this demographic is low, there is a tendency to reduce the overall radiation burden. Low-dose protocols have been recommended for COVID-19 patients by very few studies, with a diagnostic quality comparable to that of standard protocols. A dose reduction of up to 90% has been reported, without significant reduction in the signal-to-noise or contrast-to-noise ratios[83,84]. Spectral shaping with a tin filter has been applied to reduce radiation dose. Low tube voltage (≤ 100 kV) and low tube current are desired for low-dose scanning. Automatic tube current modulation technique is preferred as it accounts for body habitus. Iterative reconstruction can further reduce radiation dose. A target of CTDIvol less than 3 mGy should be selected. A multicenter study revealed that only 1 out of 28 countries reported a median CTDIvol of less than 3 mGy, indicating that low-dose imaging has not been broadly adopted yet. Whether the use of low-dose CT should be a standard for baseline imaging or for follow-up of COVID-19 cases has yet to be determined.