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Radiographic features of COVID-19 based on an initial cohort of 96 patients in Singapore

Introduction: Chest radiographs (CXR) are widely used for the screening and management of the coronavirus disease 2019 (COVID-19). This paper determinates the radiographic features of COVID-19 based on an initial national cohort of patients. Methods: This is a retrospective review of swab-positive COVID-19 patients admitted to four different hospitals in Singapore between 22 January and 9 March 2020. Initial and follow-up CXR were reviewed by three experienced radiologists to identify the predominant pattern and distribution of lung parenchymal abnormalities. Results: In total, 347 CXR of 96 patients were reviewed. Initial CXR were abnormal in 41 out of 96 patients (42.7%). The mean time from onset of symptoms to CXR abnormality was 5.3 (range 1–21) days. The predominant pattern of lung abnormality was ground-glass opacity on initial CXR (51.2%) and consolidation on follow-up CXR (51.0%). Multifocal bilateral abnormalities in mixed central and peripheral distribution were seen in 63.4% and 59.2% of abnormal initial and followup CXR, respectively. The lower zones were involved in 90.2% of the initial CXR and 93.9% of the follow-up CXR. Conclusion: In a cohort of swab-positive patients, including those identified from contact tracing, we found the incidence of CXR abnormality to be lower than previously reported. The most common pattern was ground-glass opacity or consolidation, but mixed central and peripheral involvement was more common than peripheral involvement alone.


INTRODUCTION
Coronaviruses are enveloped positive-sense RNA viruses known to cause upper and lower respiratory tract infections in addition to gastrointestinal, hepatic and neurologic diseases. (1)(2)(3) While most infections are mild, coronaviruses have emerged as an important pathogen since the severe acute respiratory syndrome (SARS) epidemic in [2002][2003]. SARS was the first known coronavirus to cause severe respiratory illness in immunocompetent adults and has an overall mortality rate of 9.6%, (4) predominantly affecting the elderly aged above 60 years where the estimated mortality rate was as high as 43%-50%. (3) In 2012, the Middle East respiratory syndrome (MERS) emerged in Saudi Arabia with an even higher mortality rate of 37.1%. (5) In December 2019, a team from the Chinese Centre for Disease Control and Prevention investigated an emerging cluster of patients with pneumonia of unknown aetiology in the city of Wuhan, Hubei Province, China. (6) The team subsequently isolated a novel coronavirus on 7 January 2020, which was later named as SARS-CoV-2. (7,8) This new virus represents the third virus of the Coronaviridae family to cause severe respiratory disease in the healthy population.
Since then, the virus has spread worldwide and the World Health Organization (WHO) declared the outbreak to be a public health emergency of international concern on 30 January 2020. WHO subsequently named the disease 'coronavirus disease 2019' (COVID-19) on 11 February 2020. As the number of confirmed cases grew to more than 118,000 with more than 4,200 deaths worldwide, WHO declared the outbreak a pandemic on 11 March 2020. (9) Although chest radiography (CXR) is less sensitive in detecting ground-glass opacities compared to computed tomography (CT), (10) it remains an essential initial radiological investigation in the screening and management of COVID-19 pneumonia. In Singapore, reversetranscription polymerase chain reaction (RT-PCR) of respiratory samples is used as the standard for confirmatory diagnosis of COVID-19 infection. CXR is utilised for the initial detection of radiographic apparent pneumonia and triaging of suspected cases due to its easy availability, instant diagnostic capability and low cost. Moreover, radiographic resolution of abnormalities has been used as an important criterion for discharging patients from hospital among other clinical parameters. (11) CXR promptly detects cases that are complicated by acute respiratory distress syndrome (ARDS), which warrants intensive care, including mechanical ventilation. Deterioration to ARDS generally indicates a poor prognosis -Chen et al found that 11 out of 17 (64.7%) patients with ARDS died of multiorgan failure, (12)  although not encountered in our series and considered a rare complication, a case of pneumothorax was reported by Chen et al on initial CXR. (12) Despite the widespread use of CXR for managing COVID-19, there have been a limited number of studies analysing the imaging features of this imaging modality. In this article, we described the radiographic findings of COVID-19 pneumonia across a spectrum of swab-positive patients. In our discussion, we contrasted our findings for COVID-19 from reported features of other viral pneumonia, with attention to SARS and MERS, the two other lethal human coronavirus infections.

METHODS
Informed consent from study participants for this retrospective review study was waived by the Singapore Ministry of Health under the Infectious Diseases Act (Chapter 137). Between 22 January to 9 March 2020, 96 confirmed cases of COVID-19 admitted to four institutions in Singapore were included in this study. COVID-19 infection was confirmed by RT-PCR assay on two nasopharyngeal and throat swabs 24 hours apart at the National Public Health Laboratory. As little was known about the virulence of the pathogen at the onset of the pandemic, all patients were managed in negative pressure isolation rooms -91 patients at the National Centre for Infectious Diseases, three at Singapore General Hospital, one at Changi General Hospital and one at Sengkang General Hospital. Patient demographics and clinical data were collected from electronic medical records.
Radiographic examinations were obtained using digital radiography equipment (Fluorospot Compact FD; Siemens, Erlangen, Germany, and FDR Visionary Suite and FDR Go; Fujifilm, Tokyo, Japan). All radiographs were acquired using frontal projections (posteroanterior views for patients who were able to stand, and anteroposterior views for portable studies and patients who could not stand).
Initial and follow-up frontal CXR of the patients with confirmed COVID-19 were included for review. The DICOM (digital imaging and communications in medicine) images were anonymised and reviewed by three fellowship/subspeciality-trained thoracic radiologists with 12, 15 and 17 years of experience, respectively, using a 2,048 × 2,048 pixel monitor (Barco, Sunnyvale, CA, USA). For patients with multiple follow-up CXR, the radiographs were systematically reviewed by the three readers to select the radiograph deemed to have the worst findings for analysis. These radiographs were reviewed independently and the final decision was reached by consensus. The reviewers were blinded from the clinical findings of the patients.
Radiographs were assessed for the presence, predominant pattern and distribution of lung parenchymal abnormalities. The CXR were analysed and categorised as either normal or abnormal.
If abnormal, the dominant pattern of lung parenchymal abnormality was assessed, the extent of involvement was recorded as unifocal, unilateral multifocal or bilateral multifocal, and their distribution was then categorised as predominant central, peripheral or mixed.
Each lung field was divided into three zones: upper, middle or lower zones, with each zone spanning one-third of the craniocaudal distance of the lung field. An opacity was considered central if most of the abnormality was located within the medial two-thirds of the lung, and peripheral if most of it was located within the lateral one-third of the lung. The patterns of the lung parenchymal abnormalities were categorised as: consolidation (homogeneous opacification of parenchyma with obscuration of vessels); ground-glass (hazy opacification without obscuring vessels); nodular opacities (focal round opacities); or reticular opacities (linear opacities that form a mesh-like pattern). We also recorded the presence of any other associated findings such as pleural effusion, cavitation, lymphadenopathy and pneumothorax.

RESULTS
There were 52 men and 44 women in the study group (mean age 46.2  14.2 years; age range 16-79 years; Table I). 93.4% of patients were initially seen at the National Centre for Infectious Diseases, the centralised national facility designated for managing the outbreak. The majority of patients were of Chinese ethnicity, accounting for 86.5% (83/96) of the cohort. Out of the 96 patients, 8 (8.3%) had underlying diabetes mellitus and 10 (10.4%) had hypertension. The mean duration from onset of symptoms to admission was 5.7 ± 6.3 days.
In total, we reviewed 347 CXR performed on 96 patients (mean CXR 3.6  3.9; range 1-32 per patient). Mean duration from initial CXR to the follow-up CXR that was deemed to have the worst findings was 8.2 ± 9.8 days. Only one patient who required mechanical ventilation developed superimposed Klebsiella pneumonia. Mean duration from onset of symptoms for the 55 patients who presented with normal CXR at presentation was 5.9 ± 7.5 days. Of the 55 patients with normal initial CXR, 16 (29.1%) did not require follow-up radiographs because of clinical improvement. Of the remaining 39 (70.9%) patients, 13 (33.3%) subsequently showed abnormal CXR findings, with a slight majority presenting predominantly with ground-glass opacities. Table I. Summary of patient characteristics (n = 96).

*Data presented as mean ± standard deviation (range).
At the initial presentation, 41 of the 96 patients (42.7%) had abnormal CXR (Table II). The mean duration from onset of symptoms for patients who presented with abnormal CXR at initial presentation was 5.3 ± 4.7 days. The predominant pattern of lung parenchymal abnormality was ground-glass opacity on initial radiograph, and this was seen in 21 (51.2%) patients. 12 (29.3%) patients had unifocal lesions on initial presentation (Fig. 1). There was a predilection for involvement of the lower zones, as seen in 37 (90.2%) patients. Right lung involvement was more common than the left (   patients with moderate to severe features, and those with worsening respiratory status. (17) We have therefore sought to methodically study the CXR findings in our initial national cohort of patients.
In this retrospective study of the initial 96 confirmed cases of COVID-19 in Singapore, 55 (57.3%) patients were found to have normal initial CXR. This is higher compared to Wong et al's study, where 31% of the 64 patients had normal initial CXR, (18) and as quoted in the review by Hosseiny et al. (19) This discrepancy could be attributed to aggressive contact tracing as a disease containment strategy in Singapore, resulting in early detection and isolation of symptomatic COVID-19 patients. It is also lower than the reported incidence of abnormal CT findings. (20) Still, it is not unexpected given the higher sensitivity of CT for lung disease, particularly the groundglass changes that predominate in COVID-19. We believe that our reported incidence rate of abnormal CXR better reflects the spectrum of COVID-19 infections.
In our series, the middle and lower lung zones were predominantly involved, alluding to dominant lower lobe disease. These findings concur with recent publications on CT findings of COVID-19 pneumonia, which showed that multifocal bilateral lung involvementworse in the lower lobeswas the predominant abnormality. (13,(21)(22)(23)(24) Similarly, a preliminary study on the ultrasonography findings of COVID-19 pneumonia found that the posterior lungs, particularly in the lower lung fields, were commonly involved. (25) In our analysis, combined central and peripheral involvement was more common, unlike recent publications on COVID-19, which reported that peripheral distribution was more commonly observed on CT (13,(21)(22)(23)(24) and CXR. (18,19) A plausible explanation for the greater central radiographic distribution of consolidation in our series is the summation effect of the abnormalities that are located posteriorly and medially in the lower lobes on 2D analysis, which although peripheral in distribution on CT, may be projected as central, i.e. close to the hilum on CXR, as demonstrated in Fig. 4. Another factor could be our definition of peripheral involvement as the outer 1/3 of the lung field, which takes into account the curved anatomy of the thorax, and the greater volume of the periphery based on prior publications on CT findings of SARS and MERS. (26,27) The study by Wong et al defined peripheral involvement as the lateral half, (18) while the review by Hosseiny et al was an extrapolation from CT findings. (19) We opine that direct analysis of radiographic features of this novel infectionrather than based on extrapolation from CTis vital, as the two modalities differ in their sensitivity for depicting the pattern and location of lung disease.
Based on our findings, the predominant pattern of lung parenchymal abnormality was that of ground-glass opacity (51.2%) on initial presentation. This is in line with the published literature, which reported ground-glass opacities, mixed ground-glass opacities and consolidation as the predominant lung parenchymal abnormalities on CT. (13,(21)(22)(23)(24) Our results showed an almost equal proportion of ground-glass opacity and consolidation in both the initial and follow-up radiographs, with a slight predominance for ground-glass opacity. It is known that CT has higher sensitivity for detecting mild ground-glass opacities compared to CXR. However, it is not known if the detection of such mild ground-glass opacities necessarily portends a poorer prognosis. Conversely, patients with more severe disease requiring extended hospitalisation have been found to have a greater prevalence of consolidation, which can readily be appreciated on CXR. (28) The imaging features of COVID-19 have been compared with those of SARS and MERS.
The review by Hosseiny et al has highlighted the overlapping radiographic features of the three human coronavirus infections, but this was based on extrapolation of reports from CT images of COVID-19. (19) Nonetheless, our study confirms that ground-glass opacity and consolidation predominate in the lower lobe and posterior lungs in COVID-19. In a retrospective review of 138 patients with SARS in Hong Kong, Wong et al reported that 78.3% of patients had airspace opacities with ill-defined margins, which obscured the vasculature compatible with consolidation. The involved lung zones were predominantly middle (52.8%) and lower (64.8%) with peripheral location (75%) on initial radiographs. (29) Our findings showed a slight predominance of ground-glass opacity on initial radiographs, and this was the most common parenchymal abnormality in a predominantly mid-and lower-zone distribution.
However, unifocal distribution was more common in SARS, (29,30) in contrast to multifocal bilateral lung involvement seen in 63.4% of our patients. We illustrate this difference with two cases from our local institution who were diagnosed with SARS in 2003; one of them developed multifocal peripheral consolidation, while the other had unifocal consolidation (Fig. 5). MERS appeared to show similar location and distribution of lung involvement, which were unifocal and peripheral, respectively. (31) However, the predominant pattern of abnormality was reported to be ground-glass opacification in contrast to SARS (Fig. 6, Table IV).
Chung et al reported that ground-glass opacities were more common on CT, as seen in 12 out of 21 patients (57%) with COVID-19 pneumonia, while consolidation with ground-glass opacities was seen in 6 out of 21 patients (29%). (13) It was also reported that a peripheral location of opacities was common (33%). (13) Both Chung et al and Huang et al reported that multifocal bilateral lung involvement was a commonly seen pattern. (11,13) Ground-glass opacities and consolidation in subpleural regions were the predominant early CT findings in SARS, while extensive ground-glass opacities and consolidation in basilar and subpleural distributions were common in MERS. (26,27) On CT, multifocal bilateral involvement has been more commonly observed in COVID-19 pneumonia and MERS, as opposed to unifocal involvement in SARS, (11,13,26,27) although this may be confounded by the more widespread use of CT in the current pandemic.
Viral pneumonia has a variable appearance on CXR and CT. Moreover, co-infection with a bacterial pathogen or inflammatory lung disease often confounds radiologic findings.
Nevertheless, most viral pneumonia patterns exhibit similarities on the basis of viral families or viridae, as they share similar pathogenic mechanisms. (3) The finding of multifocal bilateral lung consolidation may overlap with other infective pneumonia and may therefore be difficult to distinguish on imaging. Viral pneumonia of adenovirus, herpes simplex virus and bocavirus aetiology are known to cause multifocal or diffuse bilateral lung consolidation, while cytomegalovirus pneumonia may show bilateral ground-glass opacities and airspace consolidation. (3) On CXR, influenza pneumonia typically demonstrates bilateral reticulonodular opacities with or without consolidation and predominantly involves the lower lobes; on CT, they commonly show centrilobular nodules in peripheral distribution, although ground-glass opacities and consolidation have also been described. (3,32,33) Bacterial pneumonias mainly show lobar or broncho-pneumonia and present as extensive patchy consolidations of lung parenchyma on CT, while mycoplasma pneumonia manifests as bronchial wall-thickening and centrilobular nodules. (34) SARS-CoV-2 has been described to invade the bronchioles, causing bronchiolitis and peribronchitis with subsequent distal spread, thus giving rise to initial ground-glass opacity and subsequent lobular patchy opacity when the entire secondary pulmonary lobule is involved. (35) In addition, further involvement of the interlobular interstitium results in the 'fine reticulation' sign. (35) Variable findings COVID-19 pneumonia, depending on the time course of the disease at which the imaging is taken, may pose a diagnostic challenge to radiologists. Ground-glass opacities found on initial CT were shown to progress to consolidation during the peak stage of the disease (9-13 days from onset of symptoms) before showing interval improvement after 14 days. (36) In our study, the mean duration from onset of symptoms to an abnormal CXR finding was 5.3 days. Hence, the interpretation of radiographic and CT findings in a suspected or confirmed case should be correlated with the duration of symptom onset to improve diagnostic performance.
This retrospective study is limited by a lack of correlation with patient symptoms and longterm outcome. Nevertheless, our observations of certain predominant radiographic patterns are informative in dealing with this novel respiratory tract infection, and we have also highlighted specific key differences in findings from recent publications on CXR features of COVID-19, which have been mainly limited to describing chest CT. As the current pandemic continues to evolve, we expect to better determine the natural progression of radiographic findings in relation to novel treatment regimens such as the use of anti-retroviral medications (e.g. combination of lopinavir and ritonavir). (11) In conclusion, CXR is widely used as a tool for prompt initial evaluation and subsequent management of COVID-19 pneumonia. However, its imaging features have not been as welldescribed as those for chest CT. We found the incidence of abnormal CXR on presentation to be lower and mixed central and peripheral involvement to be more common than previously reported.
Improved understanding of the patterns of radiographic findings will enhance diagnostic workflow and the appropriate use of CXR in public health measures to deal with the current pandemic.

ACKNOWLEDGEMENT
Recruitment of study participants and sample collection was funded by a seed grant from the Singapore National Medical Research Council (TR19NMR119SD; project reference number: CCGSFPOR20001). Fig. 1 A 35-year-old man with fever and cough for one day. Chest radiograph obtained at Day 1 of symptoms shows a unifocal consolidation in the right lower zone, predominantly in the infrahilar location.