Radiological manifestations from 101 patients with 2019 Novel Coronavirus Disease (COVID-19) in Hamadan, West of Iran: Typical and atypical ndings

Coronavirus disease 2019 (COVID-19) has spread widely throughout the world and become a pandemic disease. In this study we decided to investigate the chest computed tomography (CT) ndings in COVID-19 patients in Hamadan, west of Iran. Methods This cross-sectional study was conducted on 101 patients with conrmed COVID-19 infection from February to March 2020. Demographic, clinical, laboratory and chest CT information of identied COVID-19 patients were assessed.

COVID-19 is direct contact from human to human, mainly through respiratory droplets, and also through contact by the same mechanism as other common cold or in uenza viruses (3).
The symptoms of COVID-19 infection appear after an incubation period, that studies so far suggest a mean incubation period of ve days (range: 0-24 days) (4).The most common presenting clinical symptoms of COVID-19 are fever, dry cough, dyspnea, muscle soreness, and fatigue (5,6). Some of the patients reported have headache or hemoptysis and some have relatively asymptomatic (7,8).
Approximately 80% of COVID-19 infections are mild or asymptomatic, 15% are severe infection requiring oxygen and 5% are critical infections requiring ventilation and mortality is approximately 3% (9). The older patients are more likely to have respiratory failure due to severe alveolar damage. (10). The old age, male sex, and presence of comorbidities are high risk factors for poor prognosis of the disease (1).
Real time-polymerase chain reaction (RT-PCR) technique has high false negative rate and needs at least 48 hours for determination, while chest CT has high sensitivity and gives the results in the small fraction of the time (11,12). Therefore, chest CT plays an important role in early detection of chest abnormality in suspected case. These features of image CT help physicians for rapid management, planning, initiation of treatment, isolation of patients and determine severity of disease. Previous studies showed that imaging plays an important role in follow up of COVID-19 patients (13). There are few studies on imaging of COVID-19 patients and majority of them belong to China, therefore we conducted this study to observe the imaging characteristics of the COVID-19 patients in Iran.

Methods:
This cross-sectional study was performed in March 2020 in Hamadan Province, the west of Iran. The number of 101 patients with con rmed COVID-19 infection identi ed in all hospitals in the province a liated to Hamadan University of Medical Sciences were enrolled in the study. Hamadan province with an area of 19493 square kilometers in extent is located in west of Iran and had a population of 1,758,268 people; according to the national census held in 2016 by Statistical Center of Iran: http://irandataportal.syr.edu/census/census-2016 The Ethics Committee of Hamadan University of Medical Sciences was approved the study. Patients with positive RT-PCR were considered as inclusion criteria and were assessed. It should be noted that these patients have not been reported in any other submission by us or anyone else.
A checklist contains demographic, clinical, laboratory ndings and chest CT examination of identi ed COVID-19 patients were used for collecting data. Demographic and clinical data including signs, symptoms and underlying diseases history, were asked directly from the patients and when the patient was unable to respond due to a bad physical condition, the information was taken with the physician or referring to patient medical records. Biochemical blood test results were gathered by refer to the patient's medical record.
For each patient chest images were reviewed independently. All hospitalized patient underwent chest computed tomography (CT Scan) using a multi-detector CT scanner with Somatom Emotion 16 slice channels (Siemens Healthcare, Erlangen, Germany) obtained in supine position and deep inspiration state without injection of contrast media. Acquisition parameters was as following characteristics: 170-200 MAs; 110-120 kVp; collimation 0.625-5 mm and pitch, 1.2. Images were reconstructed with slice thickness 0.625-5 mm and reconstruction interval 1-3 mm sharp reconstruction kernel all images viewed with lung (width, 1500 HU; level, − 600 HU) and mediastinal window (width, 400 HU; level, 40 HU).
Two expert radiologists (with 11 and 20 years of experience in chest imaging, respectively) analyzed and reviewed all the chest radiographs and CT images on a picture archiving and communication system (PACS Marco) by consensus on controversial images. All images were evaluated for this parameters: presence of lesion, location and pattern of lung abnormality (ground glass opacity, patchy mix consolidation reticular interlobular septal thickening segment and lobe involvement, mostly and minimally involved lobe presence or absence of plural and pericardial effusion, lymphadenopathy cavitation, underlying lung disorder, presence or absence of reverse halo sign and crazy paving appearance. Ground glass opacity is de ned as increased lung density without obscuration of vascular and bronchial margin due to partial lling of air space (14). Consolidation is increased density with obscuration of bronchial and vascular structure (14). Reverse halo sign of at all sign is described as partial ring or rim consolidation around the focal ground glass opacity. Crazy pacing appearance is de ned as interlobular septal thickening in the background of ground glass opacity. Peripheral is de ned as one third of periphery of lung in trans axial plane (14).
For data analysis we used descriptive statistics including: mean (SD) for describe the continuous variables and counts and percentage for describe the categorical variables arranged in frequency table and chart. Data were analyzed using Stata 14 (StataCorp, College Station, TX, USA).

Results:
The total number of 101 COVID-19 patients with the mean age of 55.21 ± 14.08 years (range: 27-87 years) were investigated. Fifty-four (53.47%) were male. The age distribution of the patients is shown in Fig. 1 The main clinical symptoms at the early stage of illness were dry cough in 83 cases (82.18%), dyspnea in 73 cases (72.28%) and fever in 55 cases (54.46%). In regards of laboratory results, 45 (44.5%) had lymphopenia and in vast majority of them CRP were 2 plus. Clinical and laboratory ndings of investigated patients are presented in Table 1. Among total cases, common CT features were ground glass opacity (GGO), inter lobular septal thickening and patchy consolidation in 64.35%, 33.66% and 26.73% cases, respectively. Other CT features is shown in Fig. 3.
Findings at initial chest CT examination in the COVID-19 patients are presented in Table 2. Of the 101 patients, 99 patients (98.02%) had bilateral involvement, but two of them had unilateral. Ninety-six patients (95.05%) had asymmetrical laterality and the right lobe was involved in 68.32% of them. At the rst chest CT of the patients, involvements were seen in the right upper, middle and lower lobes, 39 (32.67%), 13(12.67%) and 69 (68.32%), respectively. However, the left upper and lower lobes were involved in 33 (38.61%) and 58 (57.43%), respectively. The most and least involvements were seen in the right lower lobe and right middle lobe in 58 (57.43%) and 30 (29.70%) of cases, respectively. In regards of CXR, 35 (34.65%) patients had normal CXR at the rst day of diagnosis. In relation to other radiographic features of the patients it can be noted that 10 (9.9%) cases had mild plural thickening, 2 patients (1.98%) had pneumothorax, but 6 of them (5.94%) had mild to moderate plural effusion and 2 (1.98%) patients with severe plural effusion.  (2). In this study, chest CT scan that was performed in 2-4 days after symptom onset, lung abnormality was seen in the entire chest CT scan (100% of cases). CT ndings of the patients were generally consistent with those of COVID-19 pneumonia patients in China (13).
In the present study, two patients had unilateral right lung disease (only in right lower lobe) and 98.02% showed bilateral lung involvement and in 95.05% of them asymmetrical involvement was seen. The predominant lung involvement was right lung (69%), but in 27% of the patients, left lung involvement was dominant and 5% of them showed symmetrical abnormality in both lungs. In the study of Bernheim et al. reported that 20 (17%) patients had unilateral lung involvement, but left and right lungs involvement were separately seen in 7 and 13 patients, respectively (2).
The hallmarks of novel coronavirus infection on imaging are bilateral GGO mostly peripheral, followed by mixed patchy multifocal opacity and/or consolidation. However, in the study of Adam Bernheim et al. 22% of patients had no ground -glass opacity and no consolidation (2), while in our study 55% of patient showed ground-glass opacity and 36% showed mixed ground glass opacity and patchy consolidations. In the pictorial review study by Zheng Ye et al. pure ground glass opacity between 14-96% and mixed ground glass opacity and consolidation between 19-59% were reported (22).
In this study predominant abnormality was seen in right lower lobe, which is the rst involvement.
Posterior, peripheral and subpleural abnormalities were dominant features and anteriorly located segments and lobes such as right middle lobe, an lingula and anterior segment of upper and lower lobes showed less frequent, and less severe abnormality and often this lobes and segments abnormality was seen in severe cases and later in the course of disease. In the another systematic review of imaging ndings of COVID-19 pneumonia, GGO is seen mainly in the lower lobe and less frequently in the middle lobe (23). However, in the present study, right lower lobe abnormality is often early and the rst radiologic nding in COVID-19 pneumonia. In the study of Wu J et al. (24) the most frequent pattern was GGO (91%) followed by consolidation (63%) and interlobular septal thickening (59%).
In fact, this peripheral GGO with or without mixed patchy consolidation is not characteristics for COVID-19 pneumonia. Patchy ground glass opacity and consolidation with a predominantly subpleural and/or peribronchial distribution and lower lobe predominance are the most common imaging features in organizing pneumonia in CXR and chest CT scan however can affect all lung zone (25,26), so the involvement of lungs in COVID-19 pneumonia is categorized as organizing pneumonia.
Most pulmonary lesion in the viral infection was seen with peripheral and posterior lung predominant distribution and this is not a characteristic nding for COVID-19 pneumonia. Distribution of SARS and H1N1 is also peripherally located (27,28). In the another study of Yan Li et al. on 53 patients, 51 patient con rmed case of COVID-19 (with Nucleic acid testing) and two proved case of adenovirus CT ndings were similar to COVID-19 cases and showed ill-de ned patchy GGO with segmental and subpleural distribution (29). Yan Li et al. (29) were noted the ground glass pattern and coalescence in to consolidation with predominance of lung periphery are similar to SASR and MERs infection and some other studies emphasizes the non-speci city of chest CT nding.
According to study of Koo HJ et al. in uenza pneumonia affected the lung with lower lobe predominance (30). Wang et al. also emphasized that prominent and dominant distribution of H7N9 in uenza pneumonia is the right lower lobe (15). This is nonspeci c pattern of organizing pneumonia as immune reaction and corticosteroids might suppress and disappear this type of lung abnormality. However, there is difference between in uenza and COVID-19 pneumonia in comparison with in uenza pneumonia complete consolidation in COVID-19 pneumonia is less common. In the study by Wang Q et al. most patients with H7N9 pneumonia showed complete consolidation (15).
Another point about the pattern of lung involvement is that chest CT scan manifestation is altered with the course of disease and severity (18)(19). In the present study, in mild cases and in the early stage of disease, GGO was predominant pattern and later with the progression of disease, the pattern followed by crazy paving and consolidation in chest CT. In addition, Shi et al.'s study (31) showed progression of GGO to bilateral diffuse consolidation at rst to second weeks of infection after symptom onset and peripheral and posterior lung involvements were seen 78% and 67% of cases, respectively. In addition, the most of lesions were ill de ned, composed of consolidation and ground glass opacities, and lower lobe predominance was also seen and less common nodular pattern was long the broncho vascular bundles. In the study on 121 chest CT by Adam Bernhiem et al. (2) there was a correlation between onset of clinical symptoms and chest CT scan and bilateral typical peripheral involvements in 0-2days: early, 3-5 days: intermediate and 3-12 days: late was observed in 28, 78 and 88% of patients, respectively. Reticular thickening as interlobular septal thickening is seen due to interstitial lymphocyte in ltration (18). This is the second frequent lesion in COVID-19 pneumonia (24,31). In the present study, 33% of patients showed interlobular septal thickening. Another atypical and less common nding was plural changes that as plural thickening and plural effusion were seen. The former is more frequent, 32% versus 5% (31).
In this study, plural thickening was seen in 10% and mild to moderate plural effusion was seen in 6%.
Two cases in the end stage of disease showed moderate to severe plural effusion. Reverse halo sign is seen in 5% of the patients. In the study of Bernheim et al. and Yoon et al. reported reverse halo sign in 2 and 3% of COVID-19 patients (2,21). This sign rst described as speci c nding in cryptogenic organizing pneumonia; however, recently believed this sign might have indicated an organizing pneumonitis due to some viral or fungal infection such as COVID-19 pneumonia (32).
In this study, other less frequent and atypical ndings were seen as follow: 5% of the cases showed crazy paving appearance mostly in severe cases, 5% of patients had only one lobe of segment involvement, with segmental or lobar collapse consolidation appearance, one case with peribroncho vascular in ltration, one case with typical round pneumonia, mid generalized ground glass opacity in the entire lung was seen in one patient.
There was no case with signi cant lymph adenopathy, cavitation or nodular lesion or broch ectasia. Air bronchogram only was seen in case of consolidation, pericardial effusion was seen in 5%, and also 5% had hyperaeration and in two case mild unilateral pneumothorax was seen.
There are some limitations in this study such as retrospective design and no follow up chest CT scan after recovery of patients. Therefore, it is recommended more research in the future for better evaluation of lung involvement and proper management, and follow up chest CT after completing treatment should be considered. In the study of Fei shan et al. reported that automatically quantify infected lobes and segments and followed up CT scan every 3-5 day during management (12). In a study by Kay et al. (33)recommended that focus on the encouraged researchers to evaluate other patterns of lung involvement for accurate diagnosis and atypical features of lung involvement in chest CT.

Conclusion
CXR is not sensitive method as a rst imaging in diagnosis of COVID-19 pneumonia (35% normal CXR).
Chest CT scan is very sensitive but is nonspeci c and is not characteristic. Right lower lobe, mostly posterior basal segment is the most common lobe which is involved and the right middle lobe showed minimally and least involvement. Ground glass opacity, predominantly in lower posterior and peripheral distribution, was the most imaging feature which is compatible with non-speci c organizing pnumonia and about 12% showed atypical imaging pattern. Ethic approval and consent to participate: The protocol was approved by the Committee for Human Research at the Hamadan University of Medical Sciences, Iran. written informed consent for the survey was obtained from all the patients.

Consent to publish:
Not applicable.
Availability of data and materials: It should be noted that these patients have not been reported in any other submission by us or anyone else. All supporting data is available through the corresponding author.

Competing Interest
The author claimed no con ict of interest.

Funding
Hamadan University of Medical Sciences nancially supported this study. This funding source had no role in analysis and interpretation of data; in the writing of the manuscript; nor in the decision to submit it for publication.
Author's contribution FG, SHH, FK and SK developed the original idea and the protocol, abstracted and prepared the manuscript. SK, MG, FG and SB participate in the study design and analyzed the data. SB, FEA, FG, MM, FK and MMM contributed to study design and data gathering. All authors drafted the work. All authors read and approved the nal manuscript. Age distribution of COVID-19 patients by gender Frequency of underlying diseases in the COVID-19 patients