Reviews and CommentaryFree Access

Review of the Chest CT Differential Diagnosis of Ground-Glass Opacities in the COVID Era

Published Online:https://doi.org/10.1148/radiol.2020202504

Abstract

Coronavirus disease 2019 (COVID-19), a recently emerged lower respiratory tract illness, has quickly become a pandemic. The purpose of this review is to discuss and differentiate typical imaging findings of COVID-19 from those of other diseases, which can appear similar in the first instance. The typical CT findings of COVID-19 are bilateral and peripheral predominant ground-glass opacities. As per the Fleischner Society consensus statement, CT is appropriate in certain scenarios, including for patients who are at risk for and/or develop clinical worsening. The probability that CT findings represent COVID-19, however, depends largely on the pretest probability of infection, which is in turn defined by community prevalence of infection. When the community prevalence of COVID-19 is low, a large gap exists between positive predictive values of chest CT versus those of reverse transcriptase polymerase chain reaction. This implies that with use of chest CT there are a large number of false-positive results. Imaging differentiation is important for management and isolation purposes and for appropriate disposition of patients with false-positive CT findings. Herein the authors discuss differential pathology with close imaging resemblance to typical CT imaging features of COVID-19 and highlight CT features that may help differentiate COVID-19 from other conditions.

© RSNA, 2020

Learning Objectives:

After reading the article and taking the test, the reader will be able to:

  • ■ Identify the multivariate context of appropriate use of imaging in COVID-19 pneumonia

  • ■ Specify the limitations of imaging in the diagnosis of COVID-19 pneumonia

  • ■ Describe the findings and differentiating features of other lung conditions that can be frequently mistaken for COVID-19 pneumonia

Accreditation and Designation Statement

The RSNA is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The RSNA designates this journal-based SA-CME activity for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure Statement

The ACCME requires that the RSNA, as an accredited provider of CME, obtain signed disclosure statements from the authors, editors, and reviewers for this activity. For this journal-based CME activity, author disclosures are listed at the end of this article.

Summary

Chest CT findings in coronavirus disease 2019 (COVID-19) pneumonia are variable but can be bilateral, lower lobe, and extend to the pleural surfaces; these features can be helpful in distinguishing COVID-19 pneumonia from other causes of lung abnormality.

Essentials

  • ■ Typical CT findings of coronavirus disease 2019 (COVID-19) pneumonia have a wide differential diagnosis.

  • ■ The probability that CT findings of any kind represent COVID-19 is highly dependent on the prevalence of severe acute respiratory syndrome coronavirus 2 viral infection in the community.

  • ■ Careful image analysis can aid in differentiating COVID-19 from other conditions with similar imaging features.

Introduction

An acute lower respiratory tract infection caused by the 2019 novel coronavirus was first reported in China in December 2019 (1,2). The clinical spectrum of disease with coronavirus disease 2019 (COVID-19) infection is variable and ranges from an asymptomatic infection or mild upper respiratory tract illness to severe viral pneumonia with respiratory failure and occasionally death (2). Although the case fatality ratio has been as high as 15%, the incidence of critical illness has been reported to be 7%–26% (3). Patient factors that have been associated with a higher incidence of critical illness and death include male sex, age older than 60 years, obesity, diabetes, hypertension, cardiopulmonary comorbidities, and higher d-dimer and interleukin 6 values (3).

At the time of writing this article, more than 8 million cases and 450 000 deaths worldwide have been reported. The COVID-19 pandemic has resulted in an unprecedented health care crisis with immense strain on health care resources and disruptions in both routine and emergency health care delivery (4). The lack of adequate diagnostic testing has resulted in suboptimal early detection and containment of this infection, which has contributed to rapid and widespread transmission by individuals with mild or no symptoms (5). The primary diagnostic test, reverse transcriptase polymerase chain reaction (RT-PCR) assay for COVID-19, has variable sensitivity ranging from 37% to 71% (5), depending on the rate of viral expression at the time of collection and the site of specimen collection (6). Obstacles to the use of RT-PCR testing include shortage of kits and extended processing period.

Chest CT in COVID-19 pneumonia demonstrates bilateral, peripheral, and basal predominant ground-glass opacities (GGOs) and/or consolidation in nearly 85% of patients with superimposed irregular lines and interfaces; the imaging findings peak 9–13 days after infection (7,8) (Fig 1). Subsequently, a mixed pattern evolves with crazy paving, architectural distortion, and perilobular abnormalities superimposed on GGOs with slow resolution (7) (Fig 1). Importantly, CT scans may be normal in an infected patient, particularly early in the disease (8). Atypical chest CT findings include upper lobe or peribronchovascular distribution of GGOs, cavitation, tree in bud nodules, lymphadenopathy, and pleural thickening (9). Tables 1 and 2 summarize common and uncommon CT findings of COVID-19 (1021). It is vitally important to remember that the CT imaging appearance is dependent on when CT is performed during the patient’s time course of this disease.

(a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low                     grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities                     in both lungs predominantly peripheral in distribution (arrows). These are the                     typical features of the disease that have been reported with COVID-19 infection.                     (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented                     with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d)                     support the diagnosis of viral pneumonia. The reverse transcription polymerase                     chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan                     shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in                     an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2                     diabetes who presented with generalized weakness and cough. The patient was                     found to be RT-PCR test positive for COVID-19. The patient died 9 days after                     admission. Axial (e) and coronal (f) images from chest CT show widespread                     alveolar consolidation with typical radiologic findings of acute respiratory                     distress syndrome.

Figure 1a: (a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities in both lungs predominantly peripheral in distribution (arrows). These are the typical features of the disease that have been reported with COVID-19 infection. (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d) support the diagnosis of viral pneumonia. The reverse transcription polymerase chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes who presented with generalized weakness and cough. The patient was found to be RT-PCR test positive for COVID-19. The patient died 9 days after admission. Axial (e) and coronal (f) images from chest CT show widespread alveolar consolidation with typical radiologic findings of acute respiratory distress syndrome.

(a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low                     grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities                     in both lungs predominantly peripheral in distribution (arrows). These are the                     typical features of the disease that have been reported with COVID-19 infection.                     (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented                     with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d)                     support the diagnosis of viral pneumonia. The reverse transcription polymerase                     chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan                     shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in                     an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2                     diabetes who presented with generalized weakness and cough. The patient was                     found to be RT-PCR test positive for COVID-19. The patient died 9 days after                     admission. Axial (e) and coronal (f) images from chest CT show widespread                     alveolar consolidation with typical radiologic findings of acute respiratory                     distress syndrome.

Figure 1b: (a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities in both lungs predominantly peripheral in distribution (arrows). These are the typical features of the disease that have been reported with COVID-19 infection. (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d) support the diagnosis of viral pneumonia. The reverse transcription polymerase chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes who presented with generalized weakness and cough. The patient was found to be RT-PCR test positive for COVID-19. The patient died 9 days after admission. Axial (e) and coronal (f) images from chest CT show widespread alveolar consolidation with typical radiologic findings of acute respiratory distress syndrome.

(a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low                     grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities                     in both lungs predominantly peripheral in distribution (arrows). These are the                     typical features of the disease that have been reported with COVID-19 infection.                     (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented                     with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d)                     support the diagnosis of viral pneumonia. The reverse transcription polymerase                     chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan                     shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in                     an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2                     diabetes who presented with generalized weakness and cough. The patient was                     found to be RT-PCR test positive for COVID-19. The patient died 9 days after                     admission. Axial (e) and coronal (f) images from chest CT show widespread                     alveolar consolidation with typical radiologic findings of acute respiratory                     distress syndrome.

Figure 1c: (a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities in both lungs predominantly peripheral in distribution (arrows). These are the typical features of the disease that have been reported with COVID-19 infection. (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d) support the diagnosis of viral pneumonia. The reverse transcription polymerase chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes who presented with generalized weakness and cough. The patient was found to be RT-PCR test positive for COVID-19. The patient died 9 days after admission. Axial (e) and coronal (f) images from chest CT show widespread alveolar consolidation with typical radiologic findings of acute respiratory distress syndrome.

(a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low                     grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities                     in both lungs predominantly peripheral in distribution (arrows). These are the                     typical features of the disease that have been reported with COVID-19 infection.                     (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented                     with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d)                     support the diagnosis of viral pneumonia. The reverse transcription polymerase                     chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan                     shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in                     an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2                     diabetes who presented with generalized weakness and cough. The patient was                     found to be RT-PCR test positive for COVID-19. The patient died 9 days after                     admission. Axial (e) and coronal (f) images from chest CT show widespread                     alveolar consolidation with typical radiologic findings of acute respiratory                     distress syndrome.

Figure 1d: (a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities in both lungs predominantly peripheral in distribution (arrows). These are the typical features of the disease that have been reported with COVID-19 infection. (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d) support the diagnosis of viral pneumonia. The reverse transcription polymerase chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes who presented with generalized weakness and cough. The patient was found to be RT-PCR test positive for COVID-19. The patient died 9 days after admission. Axial (e) and coronal (f) images from chest CT show widespread alveolar consolidation with typical radiologic findings of acute respiratory distress syndrome.

(a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low                     grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities                     in both lungs predominantly peripheral in distribution (arrows). These are the                     typical features of the disease that have been reported with COVID-19 infection.                     (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented                     with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d)                     support the diagnosis of viral pneumonia. The reverse transcription polymerase                     chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan                     shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in                     an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2                     diabetes who presented with generalized weakness and cough. The patient was                     found to be RT-PCR test positive for COVID-19. The patient died 9 days after                     admission. Axial (e) and coronal (f) images from chest CT show widespread                     alveolar consolidation with typical radiologic findings of acute respiratory                     distress syndrome.

Figure 1e: (a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities in both lungs predominantly peripheral in distribution (arrows). These are the typical features of the disease that have been reported with COVID-19 infection. (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d) support the diagnosis of viral pneumonia. The reverse transcription polymerase chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes who presented with generalized weakness and cough. The patient was found to be RT-PCR test positive for COVID-19. The patient died 9 days after admission. Axial (e) and coronal (f) images from chest CT show widespread alveolar consolidation with typical radiologic findings of acute respiratory distress syndrome.

(a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low                     grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities                     in both lungs predominantly peripheral in distribution (arrows). These are the                     typical features of the disease that have been reported with COVID-19 infection.                     (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented                     with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d)                     support the diagnosis of viral pneumonia. The reverse transcription polymerase                     chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan                     shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in                     an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2                     diabetes who presented with generalized weakness and cough. The patient was                     found to be RT-PCR test positive for COVID-19. The patient died 9 days after                     admission. Axial (e) and coronal (f) images from chest CT show widespread                     alveolar consolidation with typical radiologic findings of acute respiratory                     distress syndrome.

Figure 1f: (a, b) COVID 19 pneumonia: A 77-year-old male patient presented with low grade fever and shortness of breath since 1 week. Chest CT shows hazy opacities in both lungs predominantly peripheral in distribution (arrows). These are the typical features of the disease that have been reported with COVID-19 infection. (c, d) COVID-19 crazy paving. The patient is a 58-year-old man who presented with lightheadedness. Axial chest CT scan (c) and coronal chest CT scan (d) support the diagnosis of viral pneumonia. The reverse transcription polymerase chain reaction (RT-PCR) results of of COVID-19 testing were positive. CT scan shows crazy-paving pattern (arrow). (e, f) COVID-19 consolidation. CT images in an 86-year-old woman with a history of hypertension, hyperlipidemia, and type 2 diabetes who presented with generalized weakness and cough. The patient was found to be RT-PCR test positive for COVID-19. The patient died 9 days after admission. Axial (e) and coronal (f) images from chest CT show widespread alveolar consolidation with typical radiologic findings of acute respiratory distress syndrome.

Table 1: Common Chest CT Findings for COVID-19 Pneumonia

Table 1:

Table 2: Uncommon CT Findings in Isolated COVID-19 Pneumonia

Table 2:

Patients may also develop cardiac involvement with COVID-19. Risk factors that have prognostic implications for developing cardiovascular disease include advancing age, impaired immune system, or elevated levels of angiotensin-converting enzyme 2 (22). Studies have reported the presence of myocardial injury with troponin elevation in 7%–17% of hospitalized patients and 22%–31% of patients admitted to the intensive care unit (8,9,23,24). Cardiac involvement manifests as myocarditis, pericarditis and heart failure, with corresponding imaging findings on chest x-ray, CT and MRI (2527). The pathophysiology includes virus infiltration, cardiac stress, and inflammation (25,26). The left ventricular ejection fraction may be preserved or reduced. Acute coronary syndromes have been reported with a proposed mechanism of increased thrombotic activity (25).

The Fleischner consensus statement on the role of chest imaging in COVID-19 is written with a multivariate perspective of disease severity, pretest probability, risk factors for and/or evidence of disease progression, and availability of diagnostic testing (5). As per the consensus statement, CT is appropriate in establishing baseline pulmonary status and identifying underlying cardiopulmonary abnormalities in patients with moderate-to-severe disease. CT can help triage resources toward patients at risk for disease progression and may help identify a cause in case of clinical worsening. CT may also help identify an alternate diagnosis (5). CT findings concerning for COVID-19 may be found incidentally in asymptomatic patients in the setting of known community transmission. Asymptomatic carriers of COVID-19 may comprise 17.9%–33.3% of infected cases (28,29). Such patients must be directed toward RT-PCR testing.

In a resource-constrained environment with a high community burden of disease and rapid point-of-care testing either unavailable or showing negative results, CT has been used to rapidly triage patients into non COVID-19, possible COVID-19, or most likely COVID-19 (Table 3). Given the presence of CT abnormalities, the probability that the CT findings represent COVID-19 depends largely on the pretest probability of infection, which is defined by community prevalence of infection and modified by individual factors such as exposure history (5,30). If the disease prevalence is high, even atypical presentations are likely to represent COVID-19. Conversely, if the disease prevalence is low, CT findings that are otherwise quite typical of COVID-19 may be caused by another disease (30). The positive and negative predictive values, which are calculated using disease prevalence in the community, are useful to consider in comparison to sensitivity and specificity, which can only be used when the true COVID-19 status is already known. Therefore, CT diagnosis is not used in isolation without acknowledging the prevalence of disease in the community. As expected, the metrics of diagnostic performance for chest CT (positive predictive value, negative predictive value, sensitivity, and specificity) are strictly valid only for the study population from which they are obtained (30).

Table 3: Differential Diagnosis of CT Ground-Glass Opacities in the COVID-19 Era

Table 3:

Kim et al (31) performed a meta-analysis to assess the diagnostic performance of CT and RT-PCR (31). For chest CT, the positive predictive value ranged from 1.5% to 30.7% and the negative predictive value ranged from 95.4% to 99.8%. For RT-PCR, the positive predictive value ranged from 47.3% to 96.4% and the negative predictive value ranged from 96.8% to 99.9%. They reported a pooled sensitivity of 94% (95% CI: 91, 96; I2 = 95%) for chest CT and 89% (95% CI: 81, 94; I2 = 90%) for RT-PCR. The pooled specificity of chest CT was 35% (95% CI: 26, 50). They found that, given the low specificity of CT, a large gap existed between the positive predictive value of chest CT versus RT-PCR in low-prevalence areas, specifically if the disease prevalence was less than 10% (31). These results imply that the use of chest CT may result in a large number of false-positive results that may lead to further diagnostic testing, greater medical cost, and workload and patient anxiety. Patients with suspected COVID-19 on chest CT scans may be placed in dedicated COVID-19 rule-out units and may experience delay in care or intervention. Thus, attempts at differentiation of chest CT abnormalities are important for management and isolation of patients with high clinical suspicion as well as for appropriate disposition of patients in whom disease prevalence or pretest probability is low.

Given the lack of specificity of chest CT findings for COVID-19, the purpose of this review is to address the range of pulmonary disease processes that can mimic the CT appearance of COVID-19 pneumonia.

Infections

Bacterial Pneumonias

Bacterial pneumonia is commonly encountered in clinical practice. Pneumonia is the eighth leading cause of death and the number one cause of death from infectious disease in the United States. Bacterial pneumonias are classified into three main groups: community-acquired pneumonia, aspiration and nosocomial pneumonia, and hospital-acquired pneumonia. Patients typically present with fever, chills, or cough. Chest radiography is the most commonly used imaging tool in pneumonias. CT should be used in unresolved cases or when complications are suspected. The usual pattern of community-acquired pneumonia is that of lobar consolidation. The radiographic patterns of nosocomial pneumonia are very variable, most commonly showing patchy consolidation, and are associated with cavitation and pleural effusion (32) (Fig 2). Patients typically have a high white cell count unless they have neutropenia or are immunocompromised.

Bacterial pneumonia. CT images in a 64-year-old woman who presented                         with substantial shortness of breath. The patient was noted to have                         bacteremia secondary to pseudomonas. (a) Axial and (b) coronal chest CT                         scans in lung windows show mixed ground-glass opacities and consolidation in                         the right upper lobe with cavitation (arrow).

Figure 2a: Bacterial pneumonia. CT images in a 64-year-old woman who presented with substantial shortness of breath. The patient was noted to have bacteremia secondary to pseudomonas. (a) Axial and (b) coronal chest CT scans in lung windows show mixed ground-glass opacities and consolidation in the right upper lobe with cavitation (arrow).

Bacterial pneumonia. CT images in a 64-year-old woman who presented                         with substantial shortness of breath. The patient was noted to have                         bacteremia secondary to pseudomonas. (a) Axial and (b) coronal chest CT                         scans in lung windows show mixed ground-glass opacities and consolidation in                         the right upper lobe with cavitation (arrow).

Figure 2b: Bacterial pneumonia. CT images in a 64-year-old woman who presented with substantial shortness of breath. The patient was noted to have bacteremia secondary to pseudomonas. (a) Axial and (b) coronal chest CT scans in lung windows show mixed ground-glass opacities and consolidation in the right upper lobe with cavitation (arrow).

In contrast to COVID-19, bacterial pneumonia characteristically produces focal segmental or lobar pulmonary opacities without lower lung predominance. Complications or associated findings such as cavitation, lung abscess, lymphadenopathy, parapneumonic effusions and empyema, when present, are useful imaging differentiating features, as they are not seen in COVID-19 unless the patients are superinfected with bacterial pneumonia (8).

Viral Pneumonias

Viruses are the most common causes of respiratory tract infections and are seen more commonly in children, the elderly, and the immunocompromised (33,34). The most common pathogen causing viral pneumonia in both immunocompetent and immunocompromised patients is influenza virus (33). The clinical signs and symptoms of viral pneumonia are often diverse and depend on host immune status (34). The spectrum of CT findings encountered in various pulmonary viral diseases encompasses four main categories: (a) GGO and consolidation; (b) nodules, micronodules, and tree-in-bud opacities; (c) interlobular septal thickening; and (d) bronchial and/or bronchiolar wall thickening (35) (Fig 3). Lymphadenopathy and pleural effusions may also be present (36). Some of the viral pneumonias can manifest as substantial GGO and include cytomegalovirus, adenovirus, herpes simplex virus, varicella zoster, measles, human meta-pneumovirus, and influenza (33,37). Percentage area of lung involvement with GGOs with different viruses has been extensively described. GGOs can be seen in 50%–75% of patients with adenovirus, in more than 75% of patients with cytomegalovirus and herpes simplex virus, and in 10%–25% of patients with human meta-pneumovirus and measles (33).

Cytomegalovirus pneumonia. CT scans in a 31-year-old woman with a                         history of type 1 diabetes mellitus complicated by end-stage renal disease.                         The patient had previously undergone kidney and pancreas transplant and                         presented with 2 days of right lower quadrant abdominal pain associated with                         nausea and vomiting. Upon further work-up, patient was found to have                         cytomegalovirus viremia. (a) Axial and (b) coronal CT images demonstrate                         diffuse randomly distributed small pulmonary nodules (arrows), many of which                         are ill-defined and distributed in the secondary pulmonary lobules and                         perilymphatic regions.

Figure 3a: Cytomegalovirus pneumonia. CT scans in a 31-year-old woman with a history of type 1 diabetes mellitus complicated by end-stage renal disease. The patient had previously undergone kidney and pancreas transplant and presented with 2 days of right lower quadrant abdominal pain associated with nausea and vomiting. Upon further work-up, patient was found to have cytomegalovirus viremia. (a) Axial and (b) coronal CT images demonstrate diffuse randomly distributed small pulmonary nodules (arrows), many of which are ill-defined and distributed in the secondary pulmonary lobules and perilymphatic regions.

Cytomegalovirus pneumonia. CT scans in a 31-year-old woman with a                         history of type 1 diabetes mellitus complicated by end-stage renal disease.                         The patient had previously undergone kidney and pancreas transplant and                         presented with 2 days of right lower quadrant abdominal pain associated with                         nausea and vomiting. Upon further work-up, patient was found to have                         cytomegalovirus viremia. (a) Axial and (b) coronal CT images demonstrate                         diffuse randomly distributed small pulmonary nodules (arrows), many of which                         are ill-defined and distributed in the secondary pulmonary lobules and                         perilymphatic regions.

Figure 3b: Cytomegalovirus pneumonia. CT scans in a 31-year-old woman with a history of type 1 diabetes mellitus complicated by end-stage renal disease. The patient had previously undergone kidney and pancreas transplant and presented with 2 days of right lower quadrant abdominal pain associated with nausea and vomiting. Upon further work-up, patient was found to have cytomegalovirus viremia. (a) Axial and (b) coronal CT images demonstrate diffuse randomly distributed small pulmonary nodules (arrows), many of which are ill-defined and distributed in the secondary pulmonary lobules and perilymphatic regions.

Of the four patterns of viral disease described earlier, the pattern that can be confused with COVID-19 is GGO as the predominant finding. Therefore, in our discussion we will focus on viruses that demonstrate predominantly this CT finding.

The viral infections most often described to have features that resemble COVID-19 include influenza, cytomegalovirus, and other coronaviruses (3841). With regard to the differentiation of COVID-19 from influenza, Liu et al (38) found that, although peripheral GGOs and consolidation are seen in both these entities, round opacities and septal thickening are more common in COVID-19. Conversely, nodules, tree-in-bud opacities, and pleural effusion are more common in influenza (38).

Li et al (20) explored differences in CT features of COVID-19 versus other Coronaviridae, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). They report that GGO, consolidation, septal thickening, and air bronchogram sign were similar in COVID-19, SARS, and MERS, whereas reversed halo sign and pulmonary nodules associated with COVID-19 have not been previously described with SARS and MERS. Lung abnormalities in SARS are more commonly reported to be unifocal (40).

Cytomegalovirus, a cause of severe lung infection in immunocompromised patients, such as those with human immunodeficiency virus (HIV) and organ transplant recipients, can result in widespread GGOs. The clinical context and timing since transplant are the best distinguishing features (33).

Human meta-pneumovirus is predominantly seen in stem cell transplant recipients and those with hematologic malignancies. Human para-influenza virus occurs in approximately 21% of patients in the intensive care unit, and bacterial co-infection is a known association (42). Human meta-pneumovirus pneumonia shows multifocal patchy consolidation with GGO on CT scans. Centrilobular nodules and bronchial wall thickening, seen in 25% of human meta-pneumonovirus pneumonia, are useful differentiating features (43).

Overall, according to Bai et al (17), compared to non-COVID-19 viral pneumonia, parenchymal opacities in COVID-19 pneumonia were more likely to be peripheral (80% vs 57%), and have GGO (91% vs 68%), fine reticular opacity (56% vs 22%) and vascular thickening (11% vs 1%). COVID-19 patients were less likely to have central and peripheral distribution (14% vs 35%), air bronchograms (14% vs 23%), pleural thickening (15% vs 33%), pleural effusion (4% vs 39%) and lymphadenopathy (2.7% vs 10.2%) (17).

Pneumocystis Pneumonia

Pneumocystis jirovecii pneumonia (PJP) is a common opportunistic infection that causes pneumonia in immunocompromised patients and, rarely, in immunocompetent individuals. It typically occurs with CD4 counts less than 200 cells per millimeter (44). The presentation of PJP in a patient with HIV infection is typically subacute, characterized by a slow onset of dry cough and dyspnea. PJP in patients without HIV infection presents as an acute illness associated with severe hypoxia and results in rapid respiratory deterioration and respiratory failure (45). The radiographic findings of PJP are nonspecific, and in as many as one-third of infected patients they may be normal (46).The most common high-resolution CT finding of PJP is diffuse GGO, which is often greater in extent in patients without HIV infection (45). With more advanced disease, crazy-paving pattern, consolidation, nodules, and cysts can also develop. Lung consolidation is more common in patients without HIV infection (47) (Fig 4).

Pneumocystis carinii pneumonia. CT scans in a 32-year-old man with                             acquired immunodeficiency syndrome and a CD4 count of 7cells per                             microliter who presented with respiratory arrest. (a) Axial and (b)                             coronal images in lung windows demonstrate a moderate right pneumothorax                             (*) and widespread ground-glass and airspace opacities.

Figure 4a: Pneumocystis carinii pneumonia. CT scans in a 32-year-old man with acquired immunodeficiency syndrome and a CD4 count of 7cells per microliter who presented with respiratory arrest. (a) Axial and (b) coronal images in lung windows demonstrate a moderate right pneumothorax (*) and widespread ground-glass and airspace opacities.

Pneumocystis carinii pneumonia. CT scans in a 32-year-old man with                             acquired immunodeficiency syndrome and a CD4 count of 7cells per                             microliter who presented with respiratory arrest. (a) Axial and (b)                             coronal images in lung windows demonstrate a moderate right pneumothorax                             (*) and widespread ground-glass and airspace opacities.

Figure 4b: Pneumocystis carinii pneumonia. CT scans in a 32-year-old man with acquired immunodeficiency syndrome and a CD4 count of 7cells per microliter who presented with respiratory arrest. (a) Axial and (b) coronal images in lung windows demonstrate a moderate right pneumothorax (*) and widespread ground-glass and airspace opacities.

Unlike COVID-19, PJP predominantly affects immunosuppressed patients. Although there may be widespread GGO in PJP, in contrast to COVID-19 pneumonia it is upper lobe predominant. Nodules, cysts, and spontaneous pneumothorax can also develop.

Interstitial Lung Diseases

Nonspecific Interstitial Pneumonia

Nonspecific interstitial pneumonia (NSIP) is a common interstitial lung disease associated with a number of conditions such as connective tissue disorders (ie, systemic sclerosis, Sjögren syndrome, polymyositis, dermatomyositis, and systemic lupus erythematosus). In addition, it can be related to autoimmune diseases such as rheumatoid arthritis, primary biliary cirrhosis, graft-versus-host disease, or drug induced (48,49). NSIP typically manifests in patients aged 40–50 years and has a higher predilection in women. The symptoms are nonspecific and include chronic dyspnea and cough without sputum production. Pulmonary function tests show a restrictive pattern of decreased lung function and reduced gas exchange capacity. High-resolution CT of the chest demonstrates predominantly basilar perivascular GGOs in the earlier stages of the disease, known as cellular NSIP. As the disease progresses, fibrotic changes develop in the form of traction bronchiectasis, volume loss, architectural distortion, and subpleural irregular reticular opacity (Fig 5). A hallmark feature of NSIP on high-resolution chest CT scans is subpleural sparing; however, it is only seen in a few cases (50). Microcystic honeycombing may be seen with NSIP, where there are subpleural cystic spaces measuring less than 4 mm.

Nonspecific interstitial pneumonitis. Axial CT scan shows subpleural                         interstitial prominence (arrow), most predominant in both lower lobes, with                         associated traction bronchiectasis.

Figure 5: Nonspecific interstitial pneumonitis. Axial CT scan shows subpleural interstitial prominence (arrow), most predominant in both lower lobes, with associated traction bronchiectasis.

In comparison to COVID-19, the symptoms of NSIP are insidious in onset. There is known association with connective tissue disorders or other predisposing condition. Subpleural sparing, when present, is considered specific for NSIP. Stigmata of fibrosis (traction bronchiectasis, architectural distortion, and honeycombing) may be seen. If rapidly developing airspace consolidation or ground-glass abnormality is seen in an acutely ill patient with NSIP, one should consider the possibility of an acute exacerbation (51).

Desquamative Interstitial Pneumonia

Desquamative interstitial pneumonia is a relatively rare interstitial lung disease seen more commonly in men. It can also be related to marijuana smoke inhalation, infections such as HIV, toxins, or occupational exposure (eg, to asbestos) (5254). Patients are predominantly middle-aged with progressively worsening shortness of breath and chronic cough. The majority of these patients are smokers. High-resolution CT demonstrates predominantly peripheral and lower lobe GGOs (Fig 6). Some cases may demonstrate fine linear or reticular opacities in the peripheral and basal lung zones (55).

Desquamative interstitial pneumonitis. (a) Axial and (b) coronal lung                         window CT scans in a 64-year-old man with a history of smoking (17                         pack-years) and shortness of breath. Images show small cysts in both lower                         lobes (arrow) with surrounding interstitial prominence.

Figure 6a: Desquamative interstitial pneumonitis. (a) Axial and (b) coronal lung window CT scans in a 64-year-old man with a history of smoking (17 pack-years) and shortness of breath. Images show small cysts in both lower lobes (arrow) with surrounding interstitial prominence.

Desquamative interstitial pneumonitis. (a) Axial and (b) coronal lung                         window CT scans in a 64-year-old man with a history of smoking (17                         pack-years) and shortness of breath. Images show small cysts in both lower                         lobes (arrow) with surrounding interstitial prominence.

Figure 6b: Desquamative interstitial pneumonitis. (a) Axial and (b) coronal lung window CT scans in a 64-year-old man with a history of smoking (17 pack-years) and shortness of breath. Images show small cysts in both lower lobes (arrow) with surrounding interstitial prominence.

The strong association of desquamative interstitial pneumonia with smoking is a useful differentiating feature. Small cystic spaces may develop within the areas of GGO, and these are not usually seen with COVID-19 (56).

Organizing Pneumonia

Patients with organizing pneumonia present with a relatively short history of breathlessness. In addition, they have nonproductive cough, weight loss, malaise, and fever. Organizing pneumonia may have unilateral or bilateral lung involvement and has myriad pulmonary manifestations. The most frequent features on high-resolution CT scans include bilateral, multifocal, patchy consolidations (present in up to 90% of cases) and ground-glass abnormalities (57) (Fig 7). Less commonly, bronchovascular nodules and bronchial wall thickening can be seen. The reverse halo sign, also called the atoll sign, is considered a hallmark feature; however, it is seen in only 20% of patients (58). A perilobular pattern is seen in more than half of the patients. It appears as polygonal mainly subpleural opacities surrounded by aerated lung (59). The lung manifestations of organizing pneumonia that resemble COVID-19 disease include lower lobe, subpleural, and peribronchovascular predominant GGOs and opacities with reverse halo appearance. The former opacities are migratory in 11%–24% of patients (60).

Organizing pneumonia. (a) Axial and (b) coronal images in lung windows                         in a 43-year-old man with a history of follicular lymphoma demonstrate                         predominantly peripheral ground-glass opacities (arrow). The patient had                         undergone chemotherapy and was admitted for respiratory failure. Lung biopsy                         yielded organizing pneumonia. The patient did well on steroids and was                         discharged.

Figure 7a: Organizing pneumonia. (a) Axial and (b) coronal images in lung windows in a 43-year-old man with a history of follicular lymphoma demonstrate predominantly peripheral ground-glass opacities (arrow). The patient had undergone chemotherapy and was admitted for respiratory failure. Lung biopsy yielded organizing pneumonia. The patient did well on steroids and was discharged.

Organizing pneumonia. (a) Axial and (b) coronal images in lung windows                         in a 43-year-old man with a history of follicular lymphoma demonstrate                         predominantly peripheral ground-glass opacities (arrow). The patient had                         undergone chemotherapy and was admitted for respiratory failure. Lung biopsy                         yielded organizing pneumonia. The patient did well on steroids and was                         discharged.

Figure 7b: Organizing pneumonia. (a) Axial and (b) coronal images in lung windows in a 43-year-old man with a history of follicular lymphoma demonstrate predominantly peripheral ground-glass opacities (arrow). The patient had undergone chemotherapy and was admitted for respiratory failure. Lung biopsy yielded organizing pneumonia. The patient did well on steroids and was discharged.

The presence of predisposing conditions can suggest organizing pneumonia. In contrast to COVID-19, pulmonary opacities are often migratory. Perilobular thickening, if present, is another helpful differentiating feature. Patients typically respond to steroids.

Exposures

Inhalational

Hypersensitivity pneumonitis.—Hypersensitivity pneumonitis or extrinsic allergic alveolitis is also known as bird fancier disease, farmer lung, and hot tub lung on the basis of the inciting agent. The disease is divided into acute, subacute, and chronic types based on timing since presentation. Each of these stages has its own distinctive appearance on high-resolution CT scans, and patients may present with some degree of overlap between stages (61). In the acute phase, patients typically present with fever, cough, dyspnea of short duration, and myalgia; in the chronic stages, they present with weight loss, fatigue, exertional dyspnea, and cough possibly with clear sputum. There are subtle to more diffuse GGOs in the acute phase, which may mimic pulmonary edema (62). The subacute stage is seen weeks to months after the first exposure to the allergen. There are distinct tiny centrilobular pulmonary nodules, measuring less than 6 mm. There may be accompanying GGOs. In the fibrotic stage, there is bilateral predominantly perihilar fibrosis with mid zone predominance. The distinct feature of hypersensitivity pneumonitis is mosaic attenuation of the lungs. This pattern represents geographic areas of high attenuation interspersed with areas of low attenuation due to air trapping (head cheese sign) (Fig 8). Rarely, lung cysts may be present, related to small airways disease (63).

Hypersensitivity pneumonitis. (a) Axial and (b) coronal images from CT                         scan in lung windows in a 28-year-old woman who presented with chronic cough                         associated with shortness of breath dyspnea on exertion. She lives at home,                         where her sister has an African gray parrot. Images show widespread                         ground-glass opacities. There is hypoattenuation and hypovascularity of                         scattered secondary lobules (head cheese sign). Her clinical symptoms                         worsened, and she was diagnosed with hypersensitivity                         pneumonitis.

Figure 8a: Hypersensitivity pneumonitis. (a) Axial and (b) coronal images from CT scan in lung windows in a 28-year-old woman who presented with chronic cough associated with shortness of breath dyspnea on exertion. She lives at home, where her sister has an African gray parrot. Images show widespread ground-glass opacities. There is hypoattenuation and hypovascularity of scattered secondary lobules (head cheese sign). Her clinical symptoms worsened, and she was diagnosed with hypersensitivity pneumonitis.

Hypersensitivity pneumonitis. (a) Axial and (b) coronal images from CT                         scan in lung windows in a 28-year-old woman who presented with chronic cough                         associated with shortness of breath dyspnea on exertion. She lives at home,                         where her sister has an African gray parrot. Images show widespread                         ground-glass opacities. There is hypoattenuation and hypovascularity of                         scattered secondary lobules (head cheese sign). Her clinical symptoms                         worsened, and she was diagnosed with hypersensitivity                         pneumonitis.

Figure 8b: Hypersensitivity pneumonitis. (a) Axial and (b) coronal images from CT scan in lung windows in a 28-year-old woman who presented with chronic cough associated with shortness of breath dyspnea on exertion. She lives at home, where her sister has an African gray parrot. Images show widespread ground-glass opacities. There is hypoattenuation and hypovascularity of scattered secondary lobules (head cheese sign). Her clinical symptoms worsened, and she was diagnosed with hypersensitivity pneumonitis.

Although widespread GGO with hypersensitivity pneumonitis can appear similar to COVID-19 pneumonia, other findings, such as poorly defined centrilobular GGO, mosaic attenuation, and air trapping on expiratory images, can help distinguish the two conditions (Fig 8). In late hypersensitivity pneumonitis, mid-to-upper lung zone fibrosis may be present.

Electronic cigarette or vaping product use–associated lung injury (EVALI).—The Centers for Disease Control and Prevention identified an outbreak of a respiratory illness in patients with a history of vaping in 2019. The entity, which is mainly identified in younger patients, was named EVALI given its association with the use of electronic cigarettes (64). EVALI clinically manifests as an acute viral illness, with nearly all patients reporting respiratory symptoms. Seventy-five percent of patients also report gastrointestinal symptoms, whereas 85% reported constitutional symptoms (65). EVALI is a diagnosis of exclusion. Most patients improve on supportive treatment, although a small percentage succumb to the illness (66). At high-resolution CT, patients demonstrate bilateral and symmetric diffuse hazy GGOs with subpleural sparing and without zonal predominance (Fig 9). Upper lung zone–predominant centrilobular nodules may also be present. Later in the disease process there is evidence of organization with architectural distortion and stigmata of fibrosis (64).

Electronic cigarette or vaping product use–associated lung                         injury. (a) Axial and (b) coronal images from chest CT in lung windows in an                         18-year-old man with a history of vaping who presented with fever,                         leukocytosis, and pleuritic chest pain. Chest CT demonstrates lower lobe                         predominant airspace opacities and multiple perihilar and lower lobe                         predominant ground-glass opacities.

Figure 9a: Electronic cigarette or vaping product use–associated lung injury. (a) Axial and (b) coronal images from chest CT in lung windows in an 18-year-old man with a history of vaping who presented with fever, leukocytosis, and pleuritic chest pain. Chest CT demonstrates lower lobe predominant airspace opacities and multiple perihilar and lower lobe predominant ground-glass opacities.

Electronic cigarette or vaping product use–associated lung                         injury. (a) Axial and (b) coronal images from chest CT in lung windows in an                         18-year-old man with a history of vaping who presented with fever,                         leukocytosis, and pleuritic chest pain. Chest CT demonstrates lower lobe                         predominant airspace opacities and multiple perihilar and lower lobe                         predominant ground-glass opacities.

Figure 9b: Electronic cigarette or vaping product use–associated lung injury. (a) Axial and (b) coronal images from chest CT in lung windows in an 18-year-old man with a history of vaping who presented with fever, leukocytosis, and pleuritic chest pain. Chest CT demonstrates lower lobe predominant airspace opacities and multiple perihilar and lower lobe predominant ground-glass opacities.

Most patients report their last episode of vaping the week before symptom onset. In contrast to COVID-19, the GGOs in EVALI are most pronounced centrally with conspicuous subpleural sparing. Any of the lung zones may be involved. Presence of upper lobe–predominant centrilobular nodules is another useful differentiating feature.

Drug Toxicity

There is a growing list of drugs leading to pulmonary adverse effects, with the recent addition of immunotherapy-related medications to the list. The characteristic feature of drug-induced pneumonitis is the onset of symptoms such as dry cough and breathlessness following the use of a new medication. Drug-induced pneumonitis usually occurs while the patient is taking the drug rather than after withdrawal. There are varied manifestations, including diffuse GGOs, depending on the inciting drug. The on-line website and mobile app Pneumotox is very useful to help sort out the number of drugs that can be associated with lung abnormalities (67). We have discussed the imaging appearance and differentiating features of interstitial lung disease earlier; these are common drug-related findings in the lungs. This section will focus on immune checkpoint inhibitors as pneumonitis related to these drugs bears close resemblance to COVID-19. Drug-related pneumonitis is observed in 3%–6% of patients with non–small cell lung cancer who are receiving immunotherapy (68,69). Four CT patterns have been reported: cryptogenic organizing pneumonia, NSIP, hypersensitivity pneumonitis, and acute interstitial pneumonia (Fig 10).

Drug-induced pneumonitis. (a) Axial and (b) coronal CT images in lung                         windows in a 61-year-old woman with history of stage IIIA non–small                         cell lung cancer. The patient had undergone chemoradiation followed by                         immunotherapy (durvalumab). Her course was complicated by pneumonitis. The                         patient improved with steroid treatment. Incidental note is made of dilated                         right side of heart. The patient has a recent history of acute pulmonary                         embolism with right-sided heart strain.

Figure 10a: Drug-induced pneumonitis. (a) Axial and (b) coronal CT images in lung windows in a 61-year-old woman with history of stage IIIA non–small cell lung cancer. The patient had undergone chemoradiation followed by immunotherapy (durvalumab). Her course was complicated by pneumonitis. The patient improved with steroid treatment. Incidental note is made of dilated right side of heart. The patient has a recent history of acute pulmonary embolism with right-sided heart strain.

Drug-induced pneumonitis. (a) Axial and (b) coronal CT images in lung                         windows in a 61-year-old woman with history of stage IIIA non–small                         cell lung cancer. The patient had undergone chemoradiation followed by                         immunotherapy (durvalumab). Her course was complicated by pneumonitis. The                         patient improved with steroid treatment. Incidental note is made of dilated                         right side of heart. The patient has a recent history of acute pulmonary                         embolism with right-sided heart strain.

Figure 10b: Drug-induced pneumonitis. (a) Axial and (b) coronal CT images in lung windows in a 61-year-old woman with history of stage IIIA non–small cell lung cancer. The patient had undergone chemoradiation followed by immunotherapy (durvalumab). Her course was complicated by pneumonitis. The patient improved with steroid treatment. Incidental note is made of dilated right side of heart. The patient has a recent history of acute pulmonary embolism with right-sided heart strain.

Diagnosis of drug-induced lung disease is based on the definite temporal relationship between drug intake and development of respiratory symptoms or imaging abnormality. The relationship may be difficult to establish when lung disease develops after drug withdrawal. Drug withdrawal generally results in improvement.

Miscellaneous

Pulmonary Edema

Pulmonary edema is the abnormal accumulation of fluid in the extravascular compartments of the lung and may be classified as increased hydrostatic pressure edema seen in heart failure, permeability edema with diffuse alveolar damage as seen in acute respiratory distress syndrome, permeability edema without diffuse alveolar damage, which can be seen with administration of various drugs and ingestion of toxins, or mixed edema seen in patients with stroke, status epilepticus, and subarachnoid hemorrhage (70). Symptoms include acute breathlessness, cough, wheezing, orthopnea, and paroxysmal nocturnal dyspnea. Findings of interstitial pulmonary edema are GGO and bronchovascular and interlobular septal thickening (71). Alveolar edema manifests as airspace consolidation in addition to the above findings. Pleural effusions are a frequent accompanying finding in cardiogenic pulmonary edema (72) (Fig 11).

Pulmonary edema. (a, b) Axial CT scans from chest CT in lung windows                         in a 67-year-old woman with cardiac history notable for congestive heart                         failure, coronary artery disease, aortic stenosis, and past myocardial                         infarction. The patient presented with dizziness. CT scans obtained to rule                         out pulmonary embolism demonstrate bilateral pleural effusions and pulmonary                         interstitial edema (arrows).

Figure 11a: Pulmonary edema. (a, b) Axial CT scans from chest CT in lung windows in a 67-year-old woman with cardiac history notable for congestive heart failure, coronary artery disease, aortic stenosis, and past myocardial infarction. The patient presented with dizziness. CT scans obtained to rule out pulmonary embolism demonstrate bilateral pleural effusions and pulmonary interstitial edema (arrows).

Pulmonary edema. (a, b) Axial CT scans from chest CT in lung windows                         in a 67-year-old woman with cardiac history notable for congestive heart                         failure, coronary artery disease, aortic stenosis, and past myocardial                         infarction. The patient presented with dizziness. CT scans obtained to rule                         out pulmonary embolism demonstrate bilateral pleural effusions and pulmonary                         interstitial edema (arrows).

Figure 11b: Pulmonary edema. (a, b) Axial CT scans from chest CT in lung windows in a 67-year-old woman with cardiac history notable for congestive heart failure, coronary artery disease, aortic stenosis, and past myocardial infarction. The patient presented with dizziness. CT scans obtained to rule out pulmonary embolism demonstrate bilateral pleural effusions and pulmonary interstitial edema (arrows).

History of an acute cardiac event or of progressive symptoms of heart failure suggests this diagnosis over COVID-19. The distribution of GGOs (usually central or gravity-dependent), lymphadenopathy, and pleural effusions in hydrostatic pulmonary edema are useful differentiating features. There may be indicators of cardiac disease at imaging, including coronary artery calcifications, cardiomegaly, and evidence of previous coronary intervention.

As mentioned previously, patients may develop pulmonary edema from COVID-19–related cardiac involvement (Fig 12) (73).

Coronavirus disease 2019 (COVID-19) with coexisting heart failure. (a)                         Axial and (c) coronal images from chest CT in lung windows in a 69-year-old                         man who presented with acute on chronic congestive heart failure with                         ejection fraction of 28%. The patient tested reverse transcription                         polymerase chain reaction positive for COVID-19. Note patchy peripherally                         distributed ground-glass opacities (arrowheads in a and c). The patient also                         has moderate bilateral pleural effusions (arrows in b).

Figure 12a: Coronavirus disease 2019 (COVID-19) with coexisting heart failure. (a) Axial and (c) coronal images from chest CT in lung windows in a 69-year-old man who presented with acute on chronic congestive heart failure with ejection fraction of 28%. The patient tested reverse transcription polymerase chain reaction positive for COVID-19. Note patchy peripherally distributed ground-glass opacities (arrowheads in a and c). The patient also has moderate bilateral pleural effusions (arrows in b).

Coronavirus disease 2019 (COVID-19) with coexisting heart failure. (a)                         Axial and (c) coronal images from chest CT in lung windows in a 69-year-old                         man who presented with acute on chronic congestive heart failure with                         ejection fraction of 28%. The patient tested reverse transcription                         polymerase chain reaction positive for COVID-19. Note patchy peripherally                         distributed ground-glass opacities (arrowheads in a and c). The patient also                         has moderate bilateral pleural effusions (arrows in b).

Figure 12b: Coronavirus disease 2019 (COVID-19) with coexisting heart failure. (a) Axial and (c) coronal images from chest CT in lung windows in a 69-year-old man who presented with acute on chronic congestive heart failure with ejection fraction of 28%. The patient tested reverse transcription polymerase chain reaction positive for COVID-19. Note patchy peripherally distributed ground-glass opacities (arrowheads in a and c). The patient also has moderate bilateral pleural effusions (arrows in b).

Coronavirus disease 2019 (COVID-19) with coexisting heart failure. (a)                         Axial and (c) coronal images from chest CT in lung windows in a 69-year-old                         man who presented with acute on chronic congestive heart failure with                         ejection fraction of 28%. The patient tested reverse transcription                         polymerase chain reaction positive for COVID-19. Note patchy peripherally                         distributed ground-glass opacities (arrowheads in a and c). The patient also                         has moderate bilateral pleural effusions (arrows in b).

Figure 12c: Coronavirus disease 2019 (COVID-19) with coexisting heart failure. (a) Axial and (c) coronal images from chest CT in lung windows in a 69-year-old man who presented with acute on chronic congestive heart failure with ejection fraction of 28%. The patient tested reverse transcription polymerase chain reaction positive for COVID-19. Note patchy peripherally distributed ground-glass opacities (arrowheads in a and c). The patient also has moderate bilateral pleural effusions (arrows in b).

Aspiration

Aspiration pneumonia occurs due to an insult from entry of a foreign substance into the respiratory tract. The foreign substance could be solid or liquid. Lung damage is mainly the result of pulmonary infection from aspiration of colonized oropharyngeal secretions. Risk factors include alcohol intoxication, general anesthesia, loss of consciousness, structural abnormalities of the pharynx and esophagus, and neuromuscular disorders (74). Clinical features range from no symptoms to severe distress with respiratory failure. Symptom onset may be acute or subacute. Acute chemical pneumonitis is characterized by a sudden onset of dyspnea, hypoxemia, tachycardia, and diffuse wheezes or crackles (75).

Aspiration can lead to the development of lobar or segmental pneumonia, bronchopneumonia, lung abscess, and empyema. In recumbent patients, the posterior segment of the upper lobes and the superior segment of the lower lobes are most commonly involved. Aspiration is more likely to involve bilateral basal segments, the middle lobe, and lingula when it occurs while the patient is upright (76). A chest radiograph may be negative early in the course of aspiration pneumonia. Komiya et al (77) reported that GGOs, centrilobular nodules, consolidation, and atelectasis are frequently noted CT findings with aspiration. Chronic aspiration results in bronchiectasis and tree-in-bud opacities (74).

There are similarities in the imaging appearance of aspiration and COVID-19 pneumonia due to involvement of peripheral portions of lungs with mixed-attenuation parenchymal opacity. The presence of centrilobular nodules, dependent tree-in-bud nodularity, and, when present, complications such as lung abscess, empyema, or visible aspirated material are helpful differentiating features. In addition, imaging findings of predisposing conditions may be present, for example, dilated esophagus, neuromuscular disorders, and anatomic abnormalities such as tracheo-esophageal fistula and head and neck malignancy (78).

Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage (DAH) occurs due to passage of blood into the alveoli. It can be seen in coagulation disorders, antiphospholipid antibody syndrome, connective tissue diseases, vasculitides, medications, inhaled toxins, pulmonary hemosiderosis, and pulmonary veno-occlusive disorders. Patients with DAH may have hemoptysis and/or anemia at laboratory testing. One-third of patients may not have hemoptysis. Bronchoalveolar lavage is usually required to confirm the diagnosis and rule out other causes for the opacities at imaging. Imaging findings depend on the chronicity of the process. Initially, DAH may manifest as GGOs. After 2–3 days, intralobular and smooth interlobular septal thickening superimpose on areas of GGOs and may sometimes give rise to a crazy-paving pattern (79) (Fig 13). In the chronic stages, the GGOs typically recede and there maybe residual centrilobular nodules.

Diffuse alveolar hemorrhage. CT scans in a 47-year-old woman with                         recurring hemoptysis. (a) Axial and (b) coronal images from chest CT in lung                         windows demonstrate widespread ground-glass opacities in both lungs                         (arrow).

Figure 13a: Diffuse alveolar hemorrhage. CT scans in a 47-year-old woman with recurring hemoptysis. (a) Axial and (b) coronal images from chest CT in lung windows demonstrate widespread ground-glass opacities in both lungs (arrow).

Diffuse alveolar hemorrhage. CT scans in a 47-year-old woman with                         recurring hemoptysis. (a) Axial and (b) coronal images from chest CT in lung                         windows demonstrate widespread ground-glass opacities in both lungs                         (arrow).

Figure 13b: Diffuse alveolar hemorrhage. CT scans in a 47-year-old woman with recurring hemoptysis. (a) Axial and (b) coronal images from chest CT in lung windows demonstrate widespread ground-glass opacities in both lungs (arrow).

There is often a history of hemoptysis and a new drop in the hemoglobin level, which favors this diagnosis. DAH is frequently associated with connective tissue disease and renal disease. Bronchoalveolar lavage shows sequentially increasing red blood cell counts. The GGOs in DAH, unlike in COVID-19, do not have a specific pattern; otherwise, imaging findings of DAH are very similar to those of COVID-19 and differentiation may only be possible on the basis of clinical history, comparison with any available prior image, and bronchoalveolar lavage or viral testing.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis is characterized by periodic acid–Schiff stain–positive material within the alveoli. It maybe idiopathic in origin, related to hematologic malignancies, and seen in immunosuppressed patients or inhalational lung disease. Typically, patients are asymptomatic or present with minimal dyspnea. Their CT chest findings are out of proportion to their clinical symptoms. Lactate dehydrogenase levels may be elevated. Pulmonary alveolar proteinosis manifests as smooth interlobular septal thickening with GGOs in both lungs, giving the characteristic “crazy-paving” appearance of the lungs (80) (Fig 14). Crazy paving in pulmonary alveolar proteinosis is widespread, with sharply marginated areas of lobular sparing.

Pulmonary alveolar proteinosis. CT scans in a 41-year-old woman who                         presented with shortness of breath and a dry cough approximately 6 months                         earlier. Now presents with continuing shortness of breath. (a) Axial and (b)                         coronal chest CT images in lung windows show extensive crazy-paving                         appearance of the lung parenchyma and ground-glass opacities with septal                         thickening. The patient underwent bronchoscopy with biopsy. Findings of                         bronchoscopy were consistent with pulmonary alveolar proteinosis.

Figure 14a: Pulmonary alveolar proteinosis. CT scans in a 41-year-old woman who presented with shortness of breath and a dry cough approximately 6 months earlier. Now presents with continuing shortness of breath. (a) Axial and (b) coronal chest CT images in lung windows show extensive crazy-paving appearance of the lung parenchyma and ground-glass opacities with septal thickening. The patient underwent bronchoscopy with biopsy. Findings of bronchoscopy were consistent with pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis. CT scans in a 41-year-old woman who                         presented with shortness of breath and a dry cough approximately 6 months                         earlier. Now presents with continuing shortness of breath. (a) Axial and (b)                         coronal chest CT images in lung windows show extensive crazy-paving                         appearance of the lung parenchyma and ground-glass opacities with septal                         thickening. The patient underwent bronchoscopy with biopsy. Findings of                         bronchoscopy were consistent with pulmonary alveolar proteinosis.

Figure 14b: Pulmonary alveolar proteinosis. CT scans in a 41-year-old woman who presented with shortness of breath and a dry cough approximately 6 months earlier. Now presents with continuing shortness of breath. (a) Axial and (b) coronal chest CT images in lung windows show extensive crazy-paving appearance of the lung parenchyma and ground-glass opacities with septal thickening. The patient underwent bronchoscopy with biopsy. Findings of bronchoscopy were consistent with pulmonary alveolar proteinosis.

Strong association with smoking and patient presentation with nonspecific symptoms and slow development of exercise intolerance guide toward pulmonary alveolar proteinosis. Unlike with COVID-19, there is no zonal predilection. Patients may recall a history of a similar episode in the past and show improvement with bronchoalveolar lavage (Fig 15).

(a, b) Coronavirus disease 2019 (COVID-19) mimicking pulmonary                         alveolar proteinosis with crazy-paving appearance. Axial chest CT scans in                         lung window in a 77-year-old man who was admitted for fever and cough.                         Images demonstrate crazy-paving appearance (arrows) mimicking pulmonary                         alveolar proteinosis. The patient’s reverse transcription polymerase                         chain reaction test was positive for COVID-19.

Figure 15a: (a, b) Coronavirus disease 2019 (COVID-19) mimicking pulmonary alveolar proteinosis with crazy-paving appearance. Axial chest CT scans in lung window in a 77-year-old man who was admitted for fever and cough. Images demonstrate crazy-paving appearance (arrows) mimicking pulmonary alveolar proteinosis. The patient’s reverse transcription polymerase chain reaction test was positive for COVID-19.

(a, b) Coronavirus disease 2019 (COVID-19) mimicking pulmonary                         alveolar proteinosis with crazy-paving appearance. Axial chest CT scans in                         lung window in a 77-year-old man who was admitted for fever and cough.                         Images demonstrate crazy-paving appearance (arrows) mimicking pulmonary                         alveolar proteinosis. The patient’s reverse transcription polymerase                         chain reaction test was positive for COVID-19.

Figure 15b: (a, b) Coronavirus disease 2019 (COVID-19) mimicking pulmonary alveolar proteinosis with crazy-paving appearance. Axial chest CT scans in lung window in a 77-year-old man who was admitted for fever and cough. Images demonstrate crazy-paving appearance (arrows) mimicking pulmonary alveolar proteinosis. The patient’s reverse transcription polymerase chain reaction test was positive for COVID-19.

Eosinophilic Pneumonia

Patients often have asthma and slow onset of fever and respiratory symptoms. The imaging appearance of this condition is classically known as “photographic negative of pulmonary edema” as the opacities are distinctly peripheral (81). The parenchymal abnormality consists of consolidation and GGO with an upper-lung predominance. Crazy paving may be present.

Clinical presentation is indolent, and middle or upper zone predilection and nonsegmental involvement are useful differentiating features.

Conclusion

The typical chest CT imaging features of coronavirus disease 2019 (COVID-19) pneumonia have low specificity due to their overlap with a number of other conditions. This review has focused on highlighting these differences with imaging examples. It is important to note that when the prevalence of COVID-19 is high, even atypical imaging features are more likely to be COVID-19. Although definitive diagnosis cannot be made based on CT imaging features alone, the use of a combination of clinical and imaging findings can substantially improve the accuracy of diagnosis.

Disclosures of Conflicts of Interest: M.P. disclosed no relevant relationships. A.D. disclosed no relevant relationships. R.B. disclosed no relevant relationships. S.K. disclosed no relevant relationships.

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Article History

Received: May 31 2020
Revision requested: June 8 2020
Revision received: June 21 2020
Accepted: June 24 2020
Published online: July 07 2020
Published in print: Dec 2020