Differences in Clinical and Imaging Features between Asymptomatic and Symptomatic COVID-19 Patients

Objectives The clinical and imaging features of asymptomatic carriers of severe acute respiratory syndrome coronavirus 2 and symptomatic COVID-19 patients. Methods The clinical and chest computed tomography imaging data of 47 asymptomatic carriers and 36 symptomatic COVID-19 patients were derived. All patients underwent 4–6 CT scans over a period of 2–5 days. Results The bulk of asymptomatic carriers who developed symptoms and most of the COVID-19 patients were older than 18 years of age with a decreased lymphocyte count, abnormal hepatic and renal function, and increased D-dimer and C-reactive protein. In the early stage, the pulmonary lesion involved mostly 1–2 lobes at the peripheral area in asymptomatic carriers but more than three lobes at both the central and peripheral areas in COVID-19 patients. In the progression stage, the lesion of asymptomatic carriers extended from the peripheral to the central area, and no significant difference was found in the lesion range compared with the symptomatic control group. In early improvement stage, the lesion was rapidly absorbed, and lesions were located primarily at the peripheral area in asymptomatic carriers; contrastingly, lesions were primarily located at both the central and peripheral areas in symptomatic patients. Asymptomatic carriers reflected a significantly shorter duration from disease onset to peak progression stage compared with the symptomatic. Conclusions Asymptomatic carriers are a potential source of transmission and may become symptomatic COVID-19 patients despite indicating less severe pulmonary damage, earlier improvement, and better prognosis. Early isolation and intervention can eliminate such carriers as potential sources of transmission and improve their prognosis.

"Asymptomatic SARS-CoV-2 carriers" refer to persons who have no clinical symptoms but have tested positive for viral nucleic acid in pharyngeal swab specimens or the positive serum-specifc immunoglobulin M antibody of the virus [15]. Tere are two situations for asymptomatic infected people: frst, the infected person has a positive nucleic acid test, and after 14 days of incubation period observation, there are no signs and symptoms of self-perception or clinical recognition, and it is always an asymptomatic infection state; second, the infected person tested positive for nucleic acid, and there were no signs and symptoms of selfperception or clinical recognition at the time of sampling, but then there was a certain clinical manifestation, that is, a "asymptomatic infection" stated in the incubation period [20]. It has been reported that approximately 30%-60% of COVID-19 patients show no symptoms or only have very mild symptoms; this does not, however, mean that these patients have a lower capability of spreading the virus [21]. In fact, the pandemic may have been caused by such covert infections. 10.9% of the asymptomatic carriers subsequently developed symptoms during the observation period to become confrmed cases. Close contact screening should not only be focused on patients who have developed illness but should also be extended to include asymptomatic cases during the incubation period to reduce the spread risk of SARS-CoV-2 [12]. Te transmission efciency of asymptomatic carriers was lower than that of confrmed cases, and it was shown to cause infection in 2.6% of those close contacts [22]. Moreover, patients who are infected with the SARS-CoV-2 virus will pass it on at a signifcant rate during the early stage of infection compared with the late stage [23]. It is thus necessary to implement early diagnosis, isolation, and treatment for asymptomatic carriers to control the infection source, cut of transmission routes, and protect the susceptible population. However, a few sets of clear data related to the current epidemic, its clinical features, and the imaging of dynamic changes among asymptomatic carriers are currently available. Accordingly, the present study was performed in conjunction with multiple centers to investigate the clinical features, imaging, and epidemic data of asymptomatic carriers to provide useful information for the management of these patients.

General Data.
Tis retrospective study was approved by the Ethics Committee of the Hebei University Hospital. Between January 2020 and March 2020, all patients who were diagnosed as having been infected with SARS-CoV-2, without presenting symptoms, were enrolled in our six hospitals.
Te inclusion criteria were patients who tested positive for the nucleic acid of the SARS-CoV-2 virus but without presenting COVID-19 pneumonia symptoms and with at least four times of complete CT images. Te patients in the asymptomatic group were all tested positive for the nucleic acid of the SARS-CoV-2 virus but without presenting symptoms (also called "asymptomatic carriers"). While the test results of the nucleic acid of the SARS-CoV-2 virus of patients in the COVID-19 group were positive, but patients had symptomatic COVID-19 pneumonia. All of the patients in the two groups were tested positive for the nucleic acid of the SARS-CoV-2 virus, and the diference between the two groups is that the asymptomatic carriers had no COVID-19 pneumonia symptoms according to the novel coronavirus protocol (the seventh edition) [24,25]. Te COVID-19 pneumonia symptoms were as follows: fever, dry cough, fatigue, nasal congestion, runny nose, sore throat, and diarrhea; most severe patients developed respiratory distress syndrome, septic shock, metabolic acidosis, and coagulation dysfunction one week after onset; mild patients presented only with low fever, mild fatigue, and no pneumonia. Te epidemic history and the typical signs of disease were extracted from medical records. All patients included were underwent multiple chest computed tomography (CT) scans, and all CT imaging data and all relevant clinical laboratory data were collected as follows: complete blood counts, D-dimer, hepatic and renal function, myocardial enzymes, and C-creative protein, according to the Novel Coronavirus protocol (the sixth edition and the seventh edition). Te leukocyte count, lymphocyte count, neutrophil/lymphocyte ratio, and C-reactive protein, these tests refect the severity of infammation; the lymphocyte count and C-reactive protein were the clinical warning index of adults. Nearly 20% of COVID-19 patients have abnormal coagulation, and almost all severe and critically ill patients have coagulation disorders, the D-dimer was tested to prevent and treat the underlying venous thromboembolism in COVID-19 patients. Abnormal myocardial enzymes indicated myocardial damage. Te abnormal myocardial enzymes responded to the degree of myocardial involvement. Te liver involvement was measured by the liver function test index (alanine aminotransferase, aspartate aminotransferase, and so on). Te kidney involvement was measured by the renal function test indicators (creatinine, urea, uric acid, and others).

Computed Tomography Scanning.
Computed tomography scanning was conducted using a GE Discovery HD750 (GE Medical Systems), Philips Brilliance 64 (Philips, Haifa, Israel), or Siemens SOMATOM Perspective (Siemens, Shanghai, China) scanner. During scanning, the patient was in the supine position with the head entering frst, and the scanning scope was set from the thoracic entrance to the level of the posterior costal diaphragm angle. For scanning with the GE Discovery HD750 scanner, the following parameters were adopted: a tube voltage of 120 kV, a tube current of 20-350 mA, a noise index of 18, a slice thickness of 5 mm, a 512 × 512 matrix, a pitch of 0.984 : 1, a lungwindow width/level of 1,500/−500 HU, and a mediastinal window of 350/40 HU; the lung window was reconstructed on the axial plane with a slice thickness of 0.625-1.250 mm. Te scanning parameters for the PHILIPS Brilliance 64 scanner included a tube voltage of 120 kV, a tube current of 50-300 mA, a 512 × 512 matrix, a pitch of 1, a lung-window width/level of 1,500/−550, a mediastinal window 350/35 HU, as well as axial plane reconstruction for the lung window.
For the SOMATOM Perspective 64 scanner, the following scanning parameters were used: a tube voltage of 120 kV, an adaptive tube current (CARE Dose 4D), a detector collimation width of 64 × 0.6 mm, and high-resolution algorithm reconstruction with a reconstruction slice thickness of 1.5 mm and a slice interval of 1.5 mm.

Computed Tomography Imaging
Analysis. Tree experienced radiologists independently evaluated chest CT imaging, and agreement was facilitated through consultation when disagreements arose. Based on quartiles of patients and degree of lung involvement from day 0 to day 26 after disease onset, in one study, four stages were identifed from the onset of initial symptoms: Stage-1 (0-4 days, n � 24); Stage-2 (5-8 days, n � 17); Stage-3 (9-13 days, n � 21); Stage-4 [23]. In another study, CT fndings of COVID-19 pneumonia are recommended to be divided into three stages: early stage, advanced stage, and severe stage according to the extent of disease involvement and manifestation [26]. According to these studies, we divided the CT images of patients in this study into three stages as follows: early stage: 0-4 days; progression stage: when the CT images of the chest improved; improvement stage: when the CT images of the chest improved; the improvement stage was further divided into the early (when the lesion showed initial improvement) and late (7-14 days after the lesion reached its most serious conditions of the CT scans) stages.
Patients who did not indicate the above typical stages were included in a special group for analysis. Te following features were used to describe chest CT imaging.
Ground-glass opacity, consolidation, ground-glass opacity mixed with consolidation, intralobular and interlobular septal thickening, the appearance of fbrous stripes, pleural efusion, mediastinal lymph node enlargement, and lesion changes during the early, progression, early improvement, and late improvement stages. (2) Pulmonary lesion distribution. Te involvement of pulmonary lobes and a decrease or increase in lesion numbers and scope concerning the progression and improvement stages. (3) Lesion location and scope. At the peripheral or subpleural area (involving the outer 1/3 of the lung), at the center, or at both the subpleural and central areas during the early, progression, and improvement stages.

Statistical Analysis.
Te SPSS Statistics 25.0 (IBM, Chicago, IL, USA) software program was used to conduct the statistical analysis. Measurement data were presented as the mean ± standard deviation and were tested using the analysis of variance and an independent t-test, whereas categorical data as frequency and tested with the chi-square test or Fisher's exact probability test. Statistical signifcance was set at P < 0.05.

Clinical and Laboratory Tests.
Forty-seven asymptomatic carriers of the SARS-CoV-2 virus were enrolled as the asymptomatic group including 30 males and 17 females with an age range of three months to 73 years (mean 37.81 ± 15.01 years) (see Figure 1 and Table 1). Concurrently, 36 symptomatic COVID-19 patients were enrolled as the control group including 25 male and 11 female participants with an age range of 6-80 years (mean 46.39 ± 16.68 years). In the control group, 13 participants had long been living in or in the nearby Wuhan area, 13 had had close contact with confrmed COVID-19 patients, and 10 had no clear epidemic history. All 47 asymptomatic carriers had had close contact with confrmed COVID-19 patients, among which 25 cases remained asymptomatic during this study, and 22 developed clinical symptoms within 2-7 days of isolation ( Figure 1). Signifcantly (P < 0.05) more patients (36%) were younger than 18 years of age among those who remained asymptomatic compared with those who developed symptoms while in isolation (4.55%) or those in the control COVID-19 group (5.56%) (see Table 1). Signifcantly (P < 0.05), more patients in the control group and among those who developed symptoms from asymptomatic carriers were older than 18 years or were elderly individuals. Concerning clinical symptoms, a sore throat had a signifcantly (P < 0.05) higher incidence (7/36, 19.44%) in the control group than among those who developed symptoms, whereas fever, cough and expectoration, headache, dizziness, fatigue, and gastrointestinal reaction were not signifcantly (P > 0.05) diferent between the control group and those who developed symptoms. Te leukocyte and lymphocyte counts, neutrophil/lymphocyte ratio, hepatic and renal function, D-dimer, and C-reactive protein results were signifcantly (P < 0.05) greater in the control patients and those who developed symptoms compared with those who remained asymptomatic. Te control group had a signifcantly (P < 0.05) higher incidence (15/36, 41.67%) of underlying diseases compared with those who remained asymptomatic (3/25, 12%) or who developed symptoms (1/22, 4.55%).

Computed Tomography Imaging.
Among the initial 47 asymptomatic carriers, 14 showed negative CT fndings related to the lungs, 19 had chest CT fndings showing typical imaging stages, and 14 did not have typical imaging stages (see Figure 1). Among 36 patients with symptomatic COVID-19, fve were mild infections with negative CT imaging, 27 had typical imaging stages, and four did not refect typical CT imaging changes.

Pulmonary Lobe Involvement.
In the early stage after disease onset, signifcantly (P < 0.05) more patients refected one-to-two lobe involvement related to pulmonary lesions in the asymptomatic group (73.68%) compared with the symptomatic group (46.67%), which involved primarily 3-4 lobes. As the disease progressed, 3-4 (15.79%) or even 5 (42.11%) lobes were involved in the asymptomatic group International Journal of Clinical Practice (see Table 2 and Figure 2(a)). No signifcant (P > 0.05) diferences were observed in the involvement of lobes at the progression and improvement stages between the asymptomatic and control groups.

Imaging Features.
In the early stage of 1-4 days after disease onset, the pulmonary lesion was mostly located at the peripheral area of the lung (73.68%) in the 19 asymptomatic carriers who had typical imaging stages (see Figures 2(b), 2(c), and 3(a)), whereas the lesion was mostly located in both the peripheral and central areas (66.67%) in 15 symptomatic patients with typical imaging stages who had received CT scanning in the early stage (Table 3 and 4 and Figure 3(b)). A signifcant (P < 0.05) diference existed concerning lesion distribution in the early stage. In the progression stage, the lesion in the asymptomatic carriers extended from the peripheral to the central area and involved both the central and peripheral areas (73.68%), with no signifcant (P > 0.05) difference observed regarding lesion range compared with the symptomatic control group (88.89%) (see Table 3 and 4).
In the early improvement stage, the lesion in the asymptomatic carriers was quickly absorbed; the lesion was generally located in the peripheral area of the lung (42.11%), and there was a signifcant diference (P < 0.05) in lesion distribution compared with symptomatic patients, whose lesions primarily involved both the central and peripheral areas (85.19%). In the late improvement stage, the lesions in both the asymptomatic and symptomatic groups were absorbed, all of which started from the central to the peripheral area; no signifcant diference (P > 0.05) in the lesion distribution between the two groups was observed. No signifcant diference (P > 0.05) was observed in the imaging features of ground-glass opacity, consolidation, and ground-glass opacity mixed with consolidation or intralobular and interlobular septal thickening between the two groups. One asymptomatic carrier had pleural efusion in the early stage, and no mediastinal lymphadenopathy nor pleural efusion occurred in the progression and improvement stages of both groups (Tables 2-4).

Comparison of the Characteristics of the Pathological
Outcome and the Time of the Progressive Outcome. In the improvement stage, the imaging features of both the asymptomatic carriers and symptomatic patients were reduced lesion extent and decreased lesion density. Te symptomatic patients showed a more signifcant (P < 0.05) reduction in the lesion extent (88.89%) compared with asymptomatic carriers (52.63%). No signifcant (P > 0.05) diference was found in the decrease of lesion density between the two groups. Te lesion number did not refect signifcant changes in the improvement stage. Te duration time from disease onset to the progression peak was signifcantly shorter (P < 0.05) in the asymptomatic carriers (4.63 ± 2.74 days) compared with the symptomatic patients (10.07 ± 3.90 days), and at the same time, the seriousness of  the disease progressed faster in the asymptomatic carriers than in the symptomatic patients, but the progression of the seriousness of the disease showed no statistical signifcance (P > 0.05) (see Table 5-7 and Figure 2(d)).
3.6. Special Cases. Among 33 asymptomatic carriers with positive pulmonary CT fndings, 14 (42.42%) did not have typical imaging stages during the disease course including 10 cases who remained asymptomatic and four who developed symptoms later. Te imaging manifestations of pulmonary lesions reached peaked at the frst time of CT scanning; however, the lesion was shown to have been gradually absorbed during follow-up CT scans (Figure 3(c)). Among 31 symptomatic COVID-19 patients with positive CT fndings, four (12.90%) did not present the typical imaging stages. In two patients, some of the pulmonary lesions were aggravated while others had been absorbed and improved. In the other two patients, new pulmonary lesions had developed, or the original lesion was aggravated at the improvement stage.

Discussion
Coronavirus 2019-related pneumonia caused by the SARS-CoV-2 virus is currently rampant worldwide. With the spread and occurrence of intergeneration changes in    International Journal of Clinical Practice 7 the virus, the clinical manifestations of patients with COVID-19 have gradually changed, and the initial symptoms of infection have become more covert. Although some patients do not present obvious discomfort or symptoms, they are as contagious as symptomatic COVID-19 patients. It has been shown that when the clinical symptoms are still mild following infection with COVID-19, the virus will replicate very actively in the pharynx and reach a peak concentration of fve days after disease onset. COVID-19 requires a much shorter time than the SARS virus to reach a peak concentration at the early stage which is 1,000 times that of the SARS virus [10]. Consequently, it is crucial that infections should be prevented, and asymptomatic patients should be treated to stop the global spread of the virus.

Clinical Features.
In this study, asymptomatic virus carriers received medical care and subsequently returned positive nucleic acid tests because they had all had close contact with confrmed COVID-19 cases. Among these patients, 46.81% subsequently developed symptoms, while 53.19% remained asymptomatic during the course of this study. Te proportion of people younger than 18 years of age among those who remained asymptomatic was signifcantly higher than those who developed symptoms or the number of symptomatic patients in the control group. Younger patients will typically have a stronger immune reaction and resistance against invading viruses compared with older patients, in whom immunosenescence may not allow the patient to produce a strong immune reaction and resistance against a novel virus [8]. Moreover, comorbidities may also play a role in decreasing the body's immune reaction and resistance against a virus [27]; the COVID-19 group had more comorbidities than asymptomatic patients and may have been more prone to infection and presenting with symptoms. In our study, patients who developed symptoms and patients in the control group had signifcantly decreased lymphocyte counts but a signifcantly increased ratio of neutrophils-to-   International Journal of Clinical Practice lymphocytes compared with those who remained asymptomatic. Lymphocyte damage may be an important factor leading to the deterioration of COVID-19 patients' condition [27]. Te ratio of neutrophils-to-lymphocytes is an independent risk factor of severe illness, particularly in the COVID-19 early stage. [28][29][30] Terefore, the timely detection of lymphocytes may help to better understand a patient's condition. It should be noted that the above discussion is only our conjecture based on the existing results. Te conclusion of immunologic backgrounds leading to asymptomatic or symptomatic disease still lacks solid evidence to support it, and further research is needed. In this study, abnormal hepatic and renal functioning was also observed in those who developed symptoms, and in the control symptomatic patients, D-dimer and C-reactive protein were signifcantly higher than in those who remained asymptomatic. Once the asymptomatic carriers developed symptoms, it indicated that the body's resistance had decreased and that the virus was able to bind to human receptors ACE2. [31] Te ACE2 receptors are expressed not only in the lower respiratory tract but also in the myocardium, as well as in the liver and kidneys; the binding of the virus to the receptor consequently causes the relevant symptoms and abnormal functioning of the organs. Concurrently, the infammatory response and C-reactive protein increased. Te degree of myocardial, liver, and kidney involvement was lower in those who remained asymptomatic compared with those who developed symptoms or in the symptomatic patients, which may have been one of the reasons that those who remained asymptomatic had quicker recovery and shorter hospitalization.

Imaging Features.
In the early stage, the pulmonary lesions involved mostly one to two lobes at the peripheral area of the lung among asymptomatic carriers but more than three lobes at both the central and peripheral areas among symptomatic patients. Tis indicated that fewer lobes and areas were involved in the asymptomatic carriers with most lesions at the peripheral or subpleural area, which is in line with the existing research. [32] In the progressive stage, the scope of ground-glass opacities increased and extended towards the central area; however, no signifcant diferences were found in the areas of involvement between the asymptomatic and symptomatic groups. In the early improvement stage, the lesion was quickly absorbed, starting from the central towards the peripheral area; the lesion was primarily located in the peripheral area (42.11%) in asymptomatic carriers. However, among the COVID-19 patients in this stage, the lesion was absorbed relatively slowly and was located primarily in both the central and peripheral areas (85.19%), and there was a signifcant difference in the lesion distribution between the two groups. In the late improvement stage, no signifcant diference was observed in lesion distribution.
Te pulmonary lesion was viral pneumonia involving lung parenchyma and interstitial infammation at all stages in both groups, with no signifcant diferences between them. In the early stage, the lesion presented primarily as  having ground-glass opacity or ground-glass opacity mixed with consolidation, with accompanying intralobular or interlobular septal thickening forming a "crazy paving" sign. Tis pathology was caused by the virus invading the pulmonary interstitial, leading to edema and thickening of the interlobular, subpleural, central, and peribronchovascular stroma. Consolidation represents further infltration of the parenchyma because the infection causes obvious shedding of alveolar epithelial cells, the formation of pulmonary hyaline membrane, exudation of alveolar fbrous cords, and infammation of the alveolar septum, resulting in increased lung density. [33].
In this study, one asymptomatic carrier had pleural efusion in the early stage, which had likely been caused by infammation involving the pleura and resulting in pleural reactive infammation. Pleural efusion was absorbed during follow-up. No mediastinal lymphadenopathy occurred in either of the two groups.
Te improvement stage was characterized by a decreased scope and density of the lesion, and COVID-19 patients showed a more signifcant decrease in the scope of lesions compared with asymptomatic carriers (88.89% vs. 52.63%, respectively). Te asymptomatic carriers had a signifcantly shorter duration from disease onset to the progression peak stage compared with COVID-19 patients (4.63 ± 2.74 vs. 10.07 ± 3.90 days, respectively), and the asymptomatic carriers also had earlier improvement compared with COVID-19 patients but with no signifcant diferences, suggesting that asymptomatic carriers typically had a short disease course with both fast progression and quick improvement.

Special Cases.
Among 33 asymptomatic carriers with positive pulmonary CT imaging, 14 (42.42%) did not have typical imaging presentations. On the frst CT scanning instance after admission, the peak progression presentations of the lesion were presented on CT imaging; in a later followup, the lesion had gradually improved or had been absorbed completely. Tis was in agreement with virological fndings indicating that patients with mild symptoms at the early stage had peak nucleic acid concentrations. [10] Following the presentation of pneumonia symptoms, the virus concentration decreased, and the patient gradually recovered with complete restoration of pulmonary CT imaging. Four COVID-19 patients also had atypical CT imaging presentations in which some lesions were absorbed, while others were aggravated, indicating continuous infltration of the virus in the lung, causing repeated pulmonary damage. In general, asymptomatic carriers had a shorter disease course and better prognosis than symptomatic patients.
Some limitations may exist in this research as follows: frstly, due to the limited cases in China recently, it is a small cohort of both asymptomatic and symptomatic participants, resulting in some bias in the research results, especially lacks the restriction of the patients' age and the matched patients between these two groups, which thus cannot fully refect all the clinical and imaging characteristics of asymptomatic and symptomatic COVID-19 patients and may cause some selection biases; secondly, the retrospective nature of this study may also have caused some bias in its outcome; thirdly, the long-term infectiveness of asymptomatic carriers was not established beyond the end date of this study and should be further investigated; fourthly, we did not pay attention to the dose of radiation of patients, and this is a multicenter study, and every hospital used diferent machines and diferent scanning conditions, so the radiation dose was diferent; ffthly, the control group used in this study is composed of participants who had symptomatic COVID-19 pneumonia and presented with clinical symptoms of COVID-19 following infection, and it would be worthwhile to add another control group composed of uninfected patients to have a base reference for pulmonary lesion distribution and localization which may call for further study; sixthly, all patients are infected by the wildtype variant, which nowadays does not play a role in the pandemic anymore, and clinical features and especially severity vary between variants, thus the data seem outdated.
In conclusion, asymptomatic carriers may be a potential source of transmission and may develop into symptomatic COVID-19 patients despite having less severe pulmonary damage, earlier improvement, and an overall better prognosis. It would be better to identify asymptomatic carriers who do not have sufcient cause for testing before the presentation of clinical symptoms to eliminate being potential sources of transmission and to improve their prognosis. Both the clinical and imaging data were signifcant in the identifcation and management of asymptomatic carriers.

Data Availability
We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for noncommercial purposes, without breaching participant confdentiality.
(3) It is crucial that infections should be prevented and asymptomatic patients.

Ethical Approval
Tis retrospective study was waived by the Ethics Committee of the Afliated Hospital of Hebei University approval because of its retrospective nature.
International Journal of Clinical Practice