Clinical Implications of 37 Childhood Cases with SARS-COV-2 Infection in Shenzhen, China

Background SARS-CoV-2 was rst identied in December 2019 in samples obtained from a 61 years old man who died of acute respiratory failure in the city of Wuhan, China with a subsequent outbreak in China. Till now, there were rare reports about childhood patients with SARS-CoV-2 infection. Methods We report 37 children diagnosed with SARS-CoV-2 infection admitted in the Third People’s hospital of Shenzhen from December 11, 2019 to February 11, 2020. Results There were 9 mild cases, 20 ordinary cases and 1 severe case and 7 cases with asymptomatic infection. The age ranged from 7 months to 17 years old and the median age was 7 years old. The median length of hospital stay is about 14 days. The time from illness onset to diagnosis ranged from 0.5 to 10 days (median time: 2 days). The common clinical features were fever (29.7%, 11/37) and cough (32.4%, 12/37). No death occurred among our patients. 86.5% (32/37) children were infected with SARS-CoV-2 after their family members (parents or grandparents). 1 child was identied with SARS-CoV-2 infection after 3 times testing. The majority (78.4%) of cases occurred in those children who travelled to Hubei Province.

median length of hospital stay is about 14 days. The time from illness onset to diagnosis ranged from 0.5 to 10 days (median time: 2 days). The common clinical features were fever (29.7%, 11/37) and cough (32.4%, 12/37). No death occurred among our patients. 86.5% (32/37) children were infected with SARS-CoV-2 after their family members (parents or grandparents). 1 child was identi ed with SARS-CoV-2 infection after 3 times testing. The majority (78.4%) of cases occurred in those children who travelled to Hubei Province.
Conclusions The majority of childhood cases with SARS-CoV-2 infection was mild or ordinary  and had travelled to Hubei Province. Family cluster transmission of SARS-CoV-2 was suspected in 86.5% of patients. Timely continuous SARS-CoV-2 pathogen testing is recommended.

Background
In December 2019, SARS-CoV-2 infection was rst reported in Wuhan, China in a 61 years old man with severe pneumonia 1 . The virus causes worldwide infections 2 , as well as family cluster and health-careassociated infections 3  Clinical classi cation and epidemic ndings: We obtained clinical data and possible exposures to COVID-19 by direct interviewing with their guardians. All symptoms, physical examination, laboratory, and image data were obtained from medical records. The patients' inclusion criteria were: (1) below 18 years old, (2) laboratory-con rmed SARS-CoV-2 infection with PCR (polymerase chain reaction) test of the virus in samples taken from the respiratory tract of the patient, and (3) patients admitted to the Third People's Hospital of Shenzhen from January 11, 2020 to February 11, 2020. Cases were classi ed as follows: (1) Asymptomatic, positive SARS-CoV-2 RNA without symptom ; (2) mild, mild clinical symptoms without pneumonia seen at chest computed tomography; (3) ordinary, fever and other respiratory symptoms with pneumonia seen at imaging; (4) severe, respiratory distress, hypoxia (oxygen saturation, ≤93%), or abnormal results of blood gas analysis (PaO2 < 0 mm Hg or PaCO2 >50 mm Hg); and (4) critical, respiratory failure requiring mechanical ventilation, shock, or other organ failure requiring intensive care unit monitoring and treatment. The exclusion criteria were suspected cases of COVID-19 without a con rmed diagnosis. All acquired data were crosschecked by two physicians to ensure that there was no duplicated data. Clinical classi cation was recommended according to the diagnostic criteria 4 .
Specimen collection: Nasopharyngeal swabs, sputum, blood and/or tracheal aspiration samples were collected into sterile containers, transferred to Center for Disease Control and Prevention (CDC) of Shenzhen and processed for detection of nucleic acid from each patient at various times. Two sets of nasopharyngeal swab samples were collected at initial diagnosis (sampling interval of at least 1 day). Follow-up sets of specimens were collected after symptoms had disappeared. SARS-CoV-2 laboratory testing: Specimens were tested using a SARS-CoV-2 real-time reverse transcription PCR (RT-qPCR) method. A licensed kit (GeneoDX Co. Ltd. Shanghai) was recommended by National microbiology Data Center of China for detection of SARS-CoV-2, (http://ivdc.chinacdc.cn/kyjz/202001/t20200121_211337.html?from=timeline&isappi nstalled=0). All PCR procedures were done at CDC of Shenzhen and the results were reported within 48 hours of collection.
During the course of hospitalization, pay attention to the changes in asymptomatic children's conditions, regularly monitor vital signs, SpO2, etc.
Data analysis: Basic descriptive analyses were carried out in all patients. A result of p value<0.05 indicated statistically signi cant. IBM SPSS statistics was used for statistical analyses.

Results
Gender and age distribution of SARS-CoV-2 infection A total of 37 patients, including 19 boys and 18 girls, met the eligible criteria. There were 9 mild cases, 20 ordinary cases, 1 severe case and 7 cases with asymptomatic infection. The male had relatively higher opportunity to be infected by COVID-19 than female, but the difference did not show signi cantly (P>0.05) (table 1). The age ranged from 7 months to 178 years old and the median age was 7 years old.
The percentage of cases in preschool and in schools was 48.6% and 51.4% respectively (P>0.05) (table 2).

Clinical manifestations, radiological and laboratory ndings of the cases
The onset clinical characteristics included fever ( 29.7%, 11/37) and cough (32.4%, 12/37. The temperature ranged from 38.0℃ to 39.0℃. Family cluster occurred in 32 cases (86.5%, 32/37). Table 3 showed the clinical manifestations, radiological and laboratory ndings of the cases. The majority of thoracic physical examination was normal but thoracic Computed Tomography (CT) showed multiple small ground-glass appearance on lower lobe of both lungs ( gure 1). Only 1 case had wheezes and hypoxia and there was no critical case. 29 cases (78.4%) had travelled to Hubei Province and 32 (86.5%) were infected with SARS-CoV-2 after their family members (parents or grandparents). 1 child's specimen was tested SARS-CoV-2 RT-qPCR for three times within two weeks and was identi ed with SARS-CoV-2 infection eventually.

Discussion
In this report, family cluster occurred in 86.5% people. The nding indicated that the family cluster transmission of SARS-CoV-2 was the main mode of transmission among children. The median length of hospital stay is about 14 days. Only one patient had no epidemiologic exposure history. The median time from illness onset to diagnosis was 2 days. 7 patients had asymptomatic infection but showed pneumonia upon thoracic CT. The lack of prominent symptoms often delayed diagnosis. The thoracic CT ndings of SARS-CoV-2 infection may present bilateral patchy densities, interstitial in ltrates, or opacities, consolidation, and pleural effusions in adults 7,8 . However, our pediatric pneumonia typically infected the lower lobes 9 . So those cases of lowerlobe pneumonia that occur during COVID-19 outbreak and had epidemiology history of exposure should be considered the possibility of SARS-CoV-2 infection.
It was reported that fever, sore throat, cough, myalgia, lymphopenia usually occurred among adult patients 10 . However, only one third of our patients presented fever. The respiratory symptoms such as cough and sputum were not prominent during the onset of the disease. Mildly increased C-reactive protein (CRP), Lactate dehydrogenase (LDH) and white blood cells (WBC) level occurred in 5 patients respectively. Only 1 patient presented neutropenia which was frequently observed in adult patients.
Previous study indicated 11 that age, viral load and blood biochemistry indexes such as, CRP and LDH may be predictors of disease severity. It was evident that childhood patients' laboratory features were not similar to adults'.
We noticed that the median time from illness onset to diagnosis was 2 days. Those children were not isolated and might be the latent source of infection before diagnosis. So early diagnosis and promptly medical isolation are needed to suspected cases.
In this report, the positive rate of SARS-CoV-2 was 89.2% at admission. 3 patients were identi ed with SARS-CoV-2 infection two days later and 1 child was con rmed infected case the third time ten days later. So those children who had a history of exposure to COVID-19 are recommended for timely continuous SARS-CoV-2 pathogen testing in order to effectively diagnose the patients and promptly to isolate the source of infection. An extensive public awareness campaign may play an important role in preventing the spread of infection.
Previously Lopinavir/Ritonavir and INF-a2b nebulization were used during the SARS 12 epidemic of 2003 and MERS of 2014 13,14 . These drugs kill viruses at high doses individually, whereas a combination of Lopinavir/ritonavir and IFN-a2b had a synergistic affection at much lower doses with possible lower toxicity 15 . SARS-CoV-2 is similar to the 2 CoVs, so therapy with Lopinavir/ritonavir and IFN-a2b may be a potential treatment for 2019-nCoV. Further study should be carried out to better understand the therapeutic effect of antiviral treatment.

Conclusions
This report suggests that family cluster transmission of COVID-19 was suspected in 86.5% of patients.
The majority of childhood cases with SARS-CoV-2 infection was mild or ordinary COVID-19 and had travelled to Hubei Province. Timely continuous SARS-CoV-2 pathogen testing is recommended.

Declarations
Ethics approval and consent to participate: The study was approved by the Ethics Committees of the Third People' Hospital of Shenzhen. Informed consent was obtained from parents or guardian for participants under 16 years old.

Consent for publication
Consent for publication obtained from guardians Availability of data and materials: All data generated or analyzed during this study are included in this published article.
Competing interests: The authors declare that they have no competing interests. Authors' contributions Y Y and XW: data collection and clinical diagnosis of patients; Y L and LL: Study design; YW: data analysis and writing. All authors read and approved the nal manuscript.