Clinical characteristics of COVID-19 in children compared with adults in Shandong, China

Aims & Background: The COVID-19 outbreak spread in China and is a threat to the world. We reported on the epidemiological, clinical, laboratory, and radiological characteristics of children cases to help health workers better understand and provide timely diagnosis and treatment. Methods: Retrospectively, two research centers’ case series of 67 consecutive hospitalized cases including 14 children cases with COVID-19 between 23 Jan 2020 to 15 Feb 2020 from Jinan and Rizhao were enrolled in this study. Epidemiological, clinical, laboratory, and radiological characteristics of children and adults were analyzed and compared. Results: Most cases in children were mild(21.4%) and conventional cases(78.6%), with mild clinical signs and symptoms, and all cases were of family clusters. Fever (35.7%) and dry cough(21.4%) were described as clinical manifestations in children cases. Dry cough and phlegm were not the most common symptoms in children compared with adults(p=0.03). In the early stages of the disease, lymphocyte counts did not significantly decline but neutrophils counts did in children compared with adults(p=0.00).There was an elevated level of LDH(p=0.01) and a lower level of CRP(p=0.00)and IL-6(p=0.01) in children compared with adults. There were 8 (57.1%)asymptomatic cases and 6 (42.9%)symptomatic cases among the 14 children cases. The age of asymptomatic patients was younger than that of symptomatic patients(p=0.03). Even among asymptomatic patients, 5(62.5%)cases had pneumonia including 3 (60%) cases with bilateral pneumonia, which was not different compared with that of asymptomatic cases(p=0.58, p=0.74). Conclusions: The clinical symptoms of children are mild, and the positive indicators of laboratory tests are rare, which may easily cause clinical misdiagnoses. The results showed that the white blood cell counts of children were all normal, with decreased neutrophil


Introduction
Since the first atypical pneumonia case was reported in Wuhan, China on December 31, 2019 [1] , the pathogen was soon identified [2] and tentatively named 2019-nCoV by the World Health Organization (WHO) [3] .On 11 Feb 2020, the World Health Organization officially named it SARS-CoV-2(Severe Acute Respiratory Syndrome Coronavirus-2) and the SARS-CoV-2 infection was named as the COVID-19(Coronavirus Disease 2019) [4] .The COVID-19 outbreak quickly spread in Wuhan city and other districts of Hubei Province with a further spread across the Chinese mainland. By 15 Feb 2020, a total of 68,584confirmed cases including 1,666 deaths were reported in China according to the Chinese Center for Disease Control and Prevention official websites and announcements [5] . COVID-19 cases were also reported in Thailand, Japan, Singapore, the Republic of Korea, Hong Kong, Taiwan, the US, and some countries in Europe [6] . The outbreak is still on-going.
Previous studies reported the main clinical characteristics of COVID-19. Fever, cough, shortness of breath, muscle ache, confusion, and headache were described as clinical manifestations. Lab tests and chest computed tomographic (CT) scans were also evaluated and the results suggested that decreased lymphocyte counts and bilateral pneumonia were common clinical features, especially in severe cases [7,8] .
At present, there is no effective anti-virus drug and vaccine for COVID-19, so early detection and isolation treatment are important to control the progression and spread of the disease. However, the current data mainly come from Hubei Province, especially from Wuhan city. Clinical features, especially in children, have not been reported outside Hubei Province.
In this study, we analyzed and compared the epidemic characteristics and clinical features in children and adults outside Hubei Province. The aims were to help health workers better understanding the clinical features of COVID-19 in children and provide timely diagnosis and treatment.

Patients
A total of 67cases including 14 children cases of confirmed COVID-19 from the Jinan infectious diseases hospital and Rizhao people's hospital, which were the designated hospitals in Jinan and Rizhao city, between 23 Jan 2020 to 15 Feb 2020 were enrolled in this study. The project was approved by the ethics board of Jinan infectious hospital (No.20200203). Informed consent was obtained from each patient or their guardian.All patients enrolled in this study were diagnosed according to the pneumonia diagnosis and treatment plan for the new coronavirus infection formulated by the National Health Commission (trial version 5) [9] .Diagnostic criteria for mild cases: mild clinical symptoms, no radiographic findings of pneumonia. Diagnostic criteria for common cases: fever, respiratory symptoms, and radiographic manifestations of pneumonia. Diagnostic criteria for severe cases: (1) respiratory distress, respiratory frequency ≥ 30 times/min; (2) hypoxemia, with resting oxygen saturation ≦93%;and (3) arterial partial oxygen pressure (PaO2)/oxygen absorption concentration (FiO2) ≦300 mmHg (1mmHg=0.133kPa).The diagnostic criteria for critical cases: (1) respiratory failure and mechanical ventilation is

Data Collection
The medical records of patients were analyzed. Information recorded included demographic data, exposure history, symptoms, signs, laboratory findings and chest computed tomographic(CT) scans. Epidemiological, clinical, laboratory, and radiological characteristics data were obtained with data collection forms from electronic medical records. The date of disease onset was defined as the day when the symptom was noticed.

RT PCR Assay for COVID-19
Throat swab specimens were collected from patients with suspected COVID-19. COVID-19 was confirmed by RT PCR using the same protocol. The dual-target detection kits were provided by the Shanghai Jienuo Company. Results: the cut-off value was 40, a Ct value <37 was positive, a Ct value >40 was negative, and 37-40 was a gray area(the diagnosis needs to be repeated). Jolla, CA, USA) were used. Measurement data were described as mean ± standard deviation. Background factors were compared using Student's -test (numerical data) or the Chi-square test (categorical data). Differences were regarded as significant if the p value was less than 0.05 on either side.

Results And Findings
Similar epidemiological and clinical characteristics of cases in Jinan and Rizhao A retrospective analysis was performed on patients in Jinan and Rizhao, Shandong Province from 23 Jun to15 Feb 2020. A total of 67 cases were enrolled in this study. The median age was 34.1years (range, 0-63years), and 32 (47.8%) were men. Most of cases were mild(11cases, 16.4%) and conventional (55cases, 82.1%), with only 1 severe case(1.5%), which were different from previous reports [7,8] associated with Wuhan city.
Considering the physical characteristics of the children, we further analyzed the difference in blood cell counts between children over 6years and adults. Lymphocyte counts showed no difference between the two groups, however, neutrophil counts decreased in both over 6 years(p=0.02) and less than 6 years in the children group compared with adults(table4).
The abnormal rate of white blood cell counts, neutrophil counts, and lymphocyte counts were also evaluated, and the results showed no difference in children compared with adults(table5    Although there were statistically significant differences in white blood cells, monocyte counts, and levels of Cr and AST between asymptomatic and symptomatic children cases, these differences were within the normal range and had no practical clinical significance. Even among asymptomatic patients, 5(62.5%)cases had pneumonia including 3 (60%) cases with bilateral pneumonia, with no difference compared with that of asymptomatic cases(p=0.58, p=0.74) (table7).

Discussion
The severe acute respiratory syndrome corona virus 2(SARS-CoV-2) infection outbreak has spread in China and around the world [10,11] . WHO defined it as a Public Health Emergency of International Concern (PHEIC).Earlier studies found that the initial patients were associated with seafood markets, and the pathogen was soon isolated from the patient's alveolar lavage and identified as anovel coronavirus [2] . Coronaviridae (CoVs) are the largest known single stranded RNA viruses. [12] They have been categorized in three groups, alpha-CoVs, beta-CoVs, and gamma-CoVs according to phylogenetic analyses and antigenic criteria. [11] The human Severe Acute Respiratory Syndrome (SARS) virus, the Middle Eastern Respiratory Syndrome (MERS) virus, and theSARS-CoV-2 all belong to beta-CoVs [13] . The bat coronavirus (BCoV) and the SARS-CoV-2share 96.2% sequence identity.
Bats were once thought to be the source of SARS-CoV-2.However, sufficient evidence is lacking.
Patients with SARS-CoV-2 infection present with a wide range of symptoms. Most patients seem to have mild disease, and about 20% appear to progress to severe disease, including pneumonia, respiratory failure, and, in some cases, even death [14] . However, most of the cases studied were from Wuhan city, and the characteristics of cases in other regions in China, especially in children, have not been reported.
A total of 67 cases including 47 cases from Jinan and 20 cases from Rizhao, of which only 1 case was the severe type and no one was in critical condition, is far lower than reported in Wuhan [15] .There were no deaths reported because of few cases of the severe or critical type. The reason for this is considered as follows: 1) There is no major epidemic in the regions except Hubei Province for strong prevention and control and 2) the virulence and pathogenicity of the virus decrease in the 2nd and 3rd generation of transmission [16] . All cases of children belong to the mild or conventional type of COVID-19, and all children are part of family clusters. Previous studies found no cases in children, who were once thought to be less susceptible [17] . According to the current trend, all people including children are susceptible to SARS-CoV-2, and person-to-person transmission develops familial clusters [18] .The reason why all children are in family clusters is that it is the traditional Chinese New Year holiday, children have less chance to have contact with the outside world, and Chinese families always attach great importance to the protection of children.
A retrospective analysis on clinical features of children of COVID-19 compared with that of adults from two research centers was made. The findings showed that clinical symptoms were mild in children with fever and dry cough being the most common symptoms, and other symptoms were rare. However, dry cough and phlegm are not the most common symptoms in children compared with adults.
Previous reports indicated that decreased lymphocytes counts were common clinical features [7,8] . However, similar results did not appear in our study, with only a total of 6 cases including 1 case of a child with decreased lymphocytes counts, and the value of lymphocytes counts showed no significant differences in children over 6 years compared with adults. On the other hand, neutrophil counts decreased in children compared with adults(p=0.02). So, lymphocyte decline is not an important indicator for the diagnosis of childhood cases and the neutrophil count decline should be focused on. SARS-CoV-2 infection may induced liver function damage, cardiac muscle damage, kidney damage, and coagulation function changes [7,8] . Among these laboratory tests, elevated LDH is more common in children than in adults, which suggested that children are more likely to suffer heart muscle damage. Elevated levels of CRP and IL-6 showed in adults, but not in children, which should attract more attention. In addition, pneumonia is not uncommon in children and is characterized by bilateral involvement, which is similar to that of adults.
However, pneumonia in adults was more severe compared with children (Fig1). Of the 14 children cases, 8 cases were asymptomatic cases. The age of asymptomatic patients was younger than that of symptomatic patients. Even among asymptomatic patients, 62.5% of cases had pneumonia. Therefore, the lung damage caused by SARS-CoV-2 is still relatively obvious.
SARS-CoV-2 belongs to lineage B beta coronavirus based on the phylogenetic analysis [19] .
The spikeprotein (S) of SARS-CoV that mediates entrance to human respiratory epithelial cells by interacting with cell surface receptor angiotensin-converting enzyme 2 (ACE2) is the most important means of pathogenesis [20,21] . The number of ACE2 receptors are significantly lower in children than in adults [21] , which may be the primary reason why children have fewer clinical symptoms and organ dysfunction than adults. In addition, the