COVID-19 pneumonia: the great radiological mimicker

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread worldwide since December 2019. Although the reference diagnostic test is a real-time reverse transcription-polymerase chain reaction (RT-PCR), chest-computed tomography (CT) has been frequently used in diagnosis because of the low sensitivity rates of RT-PCR. CT findings of COVID-19 are well described in the literature and include predominantly peripheral, bilateral ground-glass opacities (GGOs), combination of GGOs with consolidations, and/or septal thickening creating a “crazy-paving” pattern. Longitudinal changes of typical CT findings and less reported findings (air bronchograms, CT halo sign, and reverse halo sign) may mimic a wide range of lung pathologies radiologically. Moreover, accompanying and underlying lung abnormalities may interfere with the CT findings of COVID-19 pneumonia. The diseases that COVID-19 pneumonia may mimic can be broadly classified as infectious or non-infectious diseases (pulmonary edema, hemorrhage, neoplasms, organizing pneumonia, pulmonary alveolar proteinosis, sarcoidosis, pulmonary infarction, interstitial lung diseases, and aspiration pneumonia). We summarize the imaging findings of COVID-19 and the aforementioned lung pathologies that COVID-19 pneumonia may mimic. We also discuss the features that may aid in the differential diagnosis, as the disease continues to spread and will be one of our main differential diagnoses some time more.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was found to be associated with a pneumonia outbreak firstly reported in Wuhan, China, in December 2019 [1,2]. The disease subsequently called Coronavirus Disease 2019 (COVID-19) has caused a lot of cases worldwide and was declared as a pandemic by the World Health Organization (WHO) on March 11, 2020 [3].
The reference diagnostic test for COVID-19 pneumonia is real-time reverse transcription-polymerase chain reaction (RT-PCR). The specificity of RT-PCR is approximately 95%, but the sensitivity of RT-PCR at the initial presentation is 60-71% because of kit performance, sampling and transportation limitations [4][5][6]. Because of these low sensitivity rates and the need for rapid diagnosis, non-contrast chest-computed tomography (CT) has been frequently used in the current pandemic condition. Also, several cases with initial negative RT-PCR results are reported to have positive chest CT findings [4]. Although recent studies have reported the high sensitivity of chest CT for diagnosis with RT-PCR as a reference, the specificity of CT is relatively low. In a recent meta-analysis, chest CT had a pooled sensitivity of 94% and a specificity of 37% [4,5,7]. This may be explained by the fact that besides previously reported typical appearance, COVID-19 has various CT findings, and some chest CT findings of COVID-19 may closely resemble the imaging findings of some other pathologies presenting with airspace disease.
In this pictorial review, CT findings of COVID-19 pneumonia and imaging features of  pneumonia that may mimic other infectious and noninfectious diseases will be summarized.
Findings vary and usually progress during the course of the disease. In the early phase, the predominant finding is unilateral or bilateral small peripheral GGOs. While the size and number of GGOs and the number of affected lobes increase, crazy-paving pattern and consolidations appear as the disease progresses. Consolidations become denser at the peak stage ( Fig. 1). Approximately after 2 weeks, opacities start to resolve gradually, and residual subpleural curvilinear lines, fibrous stripes, and GGOs may be seen [9,12,13].

Infectious causes
Differentiation of COVID-19 pneumonia from other causes of infection is sometimes challenging, especially when it comes to viral pneumonia and other atypical pneumonia. Bai et al. reported some findings in favor of COVID-19 pneumonia rather than non-COVID pneumonia, such as the presence of GGOs, peripheral distribution, reverse halo sign, and vascular enlargement. Pleural effusion and thickening, lymphadenopathy, and central distribution are less likely to be seen in COVID-19 pneumonia [14]. By contrast, some typical findings described for COVID-19 pneumonia can be seen in non-COVID pneumonia or other pathologies. For example, both the reverse halo sign and CT halo sign have also been previously described in fungal infections and tuberculosis [15][16][17].
The diagnostic association of CT findings for different infectious diseases is summarized in Table 1.
Some typical findings of COVID-19 pneumonia, such as the subpleural distribution of opacities and a crazypaving pattern, were also described for pneumonia caused by other coronaviruses, severe acute respiratory syndrome virus (SARS), and middle east respiratory syndrome virus (MERS), that caused outbreaks previously [20][21][22]. The absence of cavitation, pleural effusion, and lymphadenopathy are common in both COVID-19 pneumonia and SARS [20].

Bacterial pneumonia
Although viral and bacterial pneumonia have overlapping imaging findings, the latter generally causes lobar/ segmental pneumonia or bronchopneumonia and focal or multifocal consolidations. Less commonly, GGOs may be seen. Peribronchial thickening, centrilobular nodular opacities, and pleural effusion are much more frequent in bacterial pneumonia than in COVID-19 pneumonia [18,23] (Fig. 2).

Fungal pneumonia
Fungal pneumonia may have various imaging findings, such as GGOs, nodular opacities, a tree-in-bud pattern, and cavitating consolidations [25,26]. A CT halo sign in which the surrounding GGOs represent hemorrhage has been commonly described in angioinvasive aspergillosis.

Table 1 CT findings of COVID-19 pneumonia and other infectious diseases
The most common findings of aforementioned disease groups are presented. Signs indicate the strength of relation between the CT finding and diagnosis; in a range of (+++) and (−−−); (+++) indicating the strongest association

Lesion distribution
Peripheral In addition, a CT halo sign may be seen in candidiasis, cryptococcosis, and coccidioidomycosis [17,26]. The reverse halo sign was previously reported in mucormycosis, invasive pulmonary aspergillosis, paracoccidioidomycosis, histoplasmosis, and cryptococcosis [15]. Although some CT findings of fungal pneumonia overlap with those of COVID-19 pneumonia, the presence of centrilobular nodular opacities, cavitation, chest wall invasion, pleural effusion, and lymphadenopathy favor the diagnosis of a fungal infection [25,26] (Fig. 3).

Non-infectious causes
The diagnostic association of CT findings for COVID-19 pneumonia and different non-infectious differential diagnoses are summarized in Table 2.

Pulmonary edema
In pulmonary edema, diffuse or patchy GGOs can be observed similar to those in COVID-19 pneumonia. However, the central and gravitational predominance of GGOs and the other accompanying findings, such as interlobular septal thickening, vascular redistribution, peribronchovascular cuffing, cardiomegaly, and pleural effusion, can help in distinguishing cardiogenic pulmonary edema from COVID-19 pneumonia [28] (Fig. 5). By contrast, COVID-19-related GGOs may interfere with asymmetrical edema findings such as mitral regurgitation-associated edema or neurogenic edema. In mitral regurgitation due to right upper pulmonary vein-directed reflux, edema findings tend to occur in the right upper lobe [29]. Neurogenic pulmonary edema can be seen in patients with brain injury, and in nearly half of the cases, parenchymal opacities are located in apices [30].

Pulmonary hemorrhage
GGOs and consolidative opacities are also commonly seen in many causes of alveolar hemorrhage, such as collagen-vascular diseases, idiopathic pulmonary hemosiderosis, vasculitis (eosinophilic granulomatosis with polyangiitis, Goodpasture syndrome, granulomatosis with polyangiitis), pulmonary contusion, and anticoagulation therapy [31,32]. (Fig. 6). Bilateral, focal, or patchy opacities and crazy-paving pattern may be observed in pulmonary hemorrhage. Other than parenchymal opacities, in pulmonary vasculitis, nodules with or without cavitation, centrilobular nodules, a CT halo sign due to perilesional hemorrhage, airway involvement, and pleural effusion may be observed [17,33]. The reverse halo sign is also reported in granulomatosis with polyangiitis [15]. Associated CT findings, patient history, clinical findings, and serologic tests are essential for differential diagnosis.
Organizing pneumonia may develop during the course of radiotherapy-induced lung disease (RILD) [45]. GGOs and/or consolidation, with superimposed septal thickening causing a crazy-paving pattern, and a CT halo sign may occur in the early phase of RILD [46,47].
Another cause of secondary organizing pneumonia is drug toxicity. Drug-induced lung diseases may present with variable imaging findings according to the underlying mechanism (hemorrhage, diffuse alveolar damage, edema, and interstitial disease) [48] (Fig. 11).

Pulmonary alveolar proteinosis
The most common CT findings of pulmonary alveolar proteinosis are bilateral, diffuse, or patchy GGOs and consolidations [49]. The crazy-paving pattern (GGOs superimposed with interlobular and intralobular septal thickening), which was recently reported in COVID-19 pneumonia, was initially described in pulmonary alveolar proteinosis [50] (Fig. 12). Increasing opacities and the presence of the pattern in COVID-19 pneumonia is thought to reflect disease progression [12].

Table 2 CT findings of COVID-19 pneumonia and non-infectious diseases
The most common findings of aforementioned disease groups are presented. Signs indicate the strength of relation between the CT finding and diagnosis; in a range of (+++) and (−−−); (+++) indicating the strongest association.

Sarcoidosis
COVID-19 pneumonia may resemble atypical sarcoidosis in some cases with patchy or nodular/mass-like GGOs, consolidations, a crazy-paving pattern, and a reverse halo sign (Fig. 13). Typical findings of sarcoidosis such as mediastinal and/or bilateral hilar lymphadenopathies and perilymphatic nodular opacities with upper lobe predilection do not match those of COVID-19 pneumonia [51,52]. In sarcoidosis, the consolidation ring of the reverse halo sign may have nodularities due to the granulomatous process [15].

Pulmonary infarction
Peripheral GGOs and the reverse halo sign of COVID-19 pneumonia may mimic pulmonary embolism-associated parenchymal changes. Preceding peripheral GGOs may also be present in patients with pulmonary embolism before consolidation develops [53]. Supporting CT findings of the pulmonary thromboembolic disease are peripheral wedge-shaped opacities, a reverse halo sign, atelectasis, and the direct visualization of intraluminal filling defects (Fig. 14). Pleural effusion may be seen [15,54].
An increased incidence of pulmonary thromboembolism is reported recently in COVID-19 pneumonia [55]. Since unenhanced chest CT is used in the routine practice of COVID-19 diagnosis, one should be alert for parenchymal pulmonary infarction findings. If the patient's condition suddenly deteriorates, pulmonary thromboembolism should be considered, and pulmonary CT angiography may be obtained.
GGOs are the most common CT finding of lymphocytic interstitial pneumonia (LIP). Unlike in COVID-19 pneumonia, diffuse distribution rather than peripheral  distribution, the presence of centrilobular nodules, lymphadenopathy, and cystic airspaces are found in LIP [58]. Acute eosinophilic pneumonia is characterized by bilateral GGOs and consolidations with random or peripheral distribution, interlobular septal thickening, and a crazy-paving pattern (Fig. 16). Pleural effusion is another commonly reported finding [59]. GGOs with lower zone predominance are also common in subacute hypersensitivity pneumonia. Additional findings such as centrilobular nodules, mosaic perfusion, and air-trapping in expiratory images can help in the differential diagnosis [60].

Aspiration pneumonia
Aspiration pneumonia also mostly involves lower lobes and the posterior lung and can manifest as patchy GGOs and/or consolidations. While the findings of bronchiolitis, such as centrilobular nodular opacities   13 The reverse halo sign in sarcoidosis and COVID-19 pneumonia. a Sarcoidosis presenting with organizing pneumonia pattern, peripheral GGOs, and reverse halo signs (arrows). b Opacities in COVID-19 pneumonia with reverse halo sign in right lower lobe (arrow). Concomitant multifocal opacities are observed and a tree-in-bud pattern, are common in aspiration pneumonia, they are not typically found in COVID-19 pneumonia [61,62] (Fig. 17). The knowledge of the patient's pre-existing conditions, general and mental status may help in the differential diagnosis.

Conclusion
Chest CT is an important tool in the diagnosis of COVID-19 pneumonia with high sensitivity rates. However, CT findings of COVID-19 pneumonia are rather nonspecific and variable during the disease course that In the same patient, pulmonary infarction is seen as a subpleural wedge-shaped opacity in the right lung (arrow). c Pulmonary CT angiography was obtained in a patient presented with shortness of breath to the emergency department. CT angiography showed subpleural opacities, but there was no thrombus in the related pulmonary artery branch (arrow). The patient's COVID-19 RT-PCR result turned out to be positive may resemble numerous infectious and non-infectious diseases. The awareness and knowledge of the radiological features of these entities are essential in early diagnosis and management of precautions during the pandemic. Duration of the symptoms, background and clinical findings of the patient, ancillary imaging findings, and followup CT imaging when needed is helpful in the differential diagnosis.