Roles of Children and Adolescents in COVID-19 Transmission in the Community: A Retrospective Analysis of Nationwide Data in Japan

Background: Roles of children and adolescents in spreading coronavirus disease 2019 (COVID-19) in the community is not fully understood. Methods: We analyzed the data of 7,758 children and adolescents with COVID-19 and characteristics of secondary transmission generated by these cases using case information published by local governments. Ratio of pediatric and adolescent cases generating secondary transmission was calculated for various social settings. Results: The incidence of COVID-19 was 24.8 cases per 105 population aged between 0 and 9 years, and 59.2 among those aged between 10 and 19 years, which was lower than that among individuals of all age groups (79.6 per 105 population) between January 15 and October 31, 2020. The proportion of cases generating secondary cases was 8.3% among infants and young children in nursery schools and kindergartens, 16% among children and adolescents attending primary schools, 34% among those attending junior high schools, 43% among those attending high schools, 31% among those attending professional training colleges, and 24% in those attending universities. Households were the most common setting for secondary transmission. Conclusion: The risk of generating secondary cases might be limited among pediatric and adolescent cases with COVID-19, especially in settings outside households. Effectiveness of traditional mitigation measures (e.g., school closures) to suppress COVID-19 transmissions should be carefully evaluated.


INTRODUCTION
Coronavirus disease 2019 (COVID-19) generally causes mild or asymptomatic infections in children and adolescents compared to older age groups (1). The incidence of COVID-19 among children and adolescents is also lower than that among adults, potentially due to multiple factors, such as different exposure patterns and gene expression profiles (2,3). In seasonal and pandemic influenza, children and adolescents play a major role in spreading the virus in the community; therefore, school closures are effective in suppressing influenza transmission (4,5). Conversely, their role in spreading COVID-19 in the community is not fully understood due to the limited information about secondary transmission generated by them (6)(7)(8). In this study, we aimed to reveal the secondary transmission rate of pediatric and adolescent cases with COVID-19 in various settings and their role in transmission dynamics in the community.

METHODS
A retrospective data analysis was conducted for patients with COVID-19 aged <20 years in Japan between January 15 and October 31, 2020. In Japan, it is mandatory to report every confirmed COVID-19 case, who were diagnosed by validated testing methods including polymerase chain reaction (PCR) using respiratory samples or saliva, quantitative antigen tests using respiratory samples or saliva, and point-of-care antigen tests using respiratory samples (9). Information about these cases (e.g., demographics, date of onset, contact with previously confirmed cases, places where contact with previously confirmed cases occurred) is posted on the local government website every day. The age of each patient is published in 10-year incremental age groups. We retrieved this information and constructed a database as previously described (Supplementary Table 1) (10,11). In the study, the age of students in primary schools, junior high schools, and high schools was defined as 7-12 years old, 13-15 years old, and 16-18 years old, respectively. The incidence of pediatric and adolescent cases was calculated for those aged between 0 and 9 years and 10 and 19 years using the population data published by Statistics Bureau of Japan (12). Five or more COVID-19 cases with known contact with previously confirmed cases in the same events or venues were defined as a cluster, based on information about places of contacts and dates of onset/confirmation, which were collected during case investigations by local public health authorities and summarized in our database. The secondary transmission rate was calculated for pediatric and adolescent cases who had no known contact with previously confirmed cases. This is because individuals who had known contact with confirmed cases before confirmation were requested to be self-quarantined before confirmation (9). Definition of a pair of primary and secondary cases was described in Supplementary Figure 1.
Statistical analysis was conducted by using R ver.3.5.0 (R Foundation for Statistical Computing, Vienna, Austria). A Student's t-test was performed to compare continuous variables between 2 groups. A p < 0.05 was considered as statistically significant.

RESULTS
In the study, we identified 7,758 confirmed cases among individuals aged 0-9 years and 10-19 years. The incidence of pediatric and adolescent cases in the study was 24.8 cases per 10 5 population (2,450/9,860 × 10 3 ) aged between 0 and 9 years, and 59.2 (6,608/11,170 × 10 3 ) among those aged between 10 and 19 years between January 15 and October 31, 2020. The numbers of pediatric and adolescent cases reached their peaks in mid-April and resurged from late-June, which was parallel to the increasing patterns of the total cases of all age groups (Figure 1). The median (interquartile range) of the duration between onset and confirmation was 4 days (3-7) among pediatric and adolescent cases, which was significantly shorter than that among the total cases of all age groups [6 days (3-9), p < 0.001]. Among 7,758 cases, 4,734 (61%) cases had contact with previously confirmed cases ( Table 1). They were presumed to have acquired infection in various settings, however, the household was the most common setting (1,521/4,734, 32%) ( Table 1).
Among 3,024 cases without known contact with previously confirmed cases, 297 cases (9.8%, 297/3,024) generated secondary cases ( Table 2). Among these 297 cases, 168 cases (57%, 168/297) generated only 1 secondary case, 118 cases (40%, 118/297) generated 2-4 cases, and 11 cases (3.7%, 11/297) generated 5-10 cases. The proportion of cases that generated secondary transmission was lower than 10% among infants and young children not attending nursery schools and those attending nursery schools and kindergartens, and lower among those attending primary schools (16%). Conversely, the proportion was higher than 20% among students in universities and workers, and higher than 30% among those attending junior high schools, high schools, and professional training colleges ( Table 2). The proportion was 2.7 and 2.1 times higher among junior high school and high school children than  Table 2). The proportion of adult cases among these secondary cases was 77% (108/141) in households and 19% (6/31) in nursery schools, kindergartens, schools, colleges, and universities ( Table 2).
In the study, we identified 72 clusters associated with pediatric and adolescent cases, among which 28 were identified in schools, professional training colleges, and universities ( Table 3). A total of 508 cases were identified in those clusters, among which  Characteristics of secondary transmission generated by pediatric and adolescent cases in various settings were summarized. *Median (interquartile range) of the number of secondary cases per case was calculated among children and adolescents who generated secondary cases. **Others included dining at restaurants and outdoor events.

DISCUSSION
We reported the secondary transmission rate of pediatric and adolescent cases with COVID-19 and their roles in transmission of COVID-19 in various settings. The incidence of pediatric and adolescent cases was lower than that of cases among individuals of all age groups (79.6 cases per 10 5 population [100,436/126,167 × 10 3 )] in our database, which was in line with previous studies in other countries (13). In contrast to the 2009 H1N1 pandemic, in which children and adolescents were the most affected age groups, their risks of acquiring infection were assumed to be limited for COVID-19 (14). The significantly shorter duration between onset and confirmation than older age groups was potentially because most of the infected children and adolescents were identified as close contacts of previously confirmed cases. This also might be contributing to high proportions of asymptomatic cases among children and adolescents with COVID-19. Furthermore, the most common setting where pediatric and adolescent cases generated secondary transmission was their households. Our results suggest their limited capacities to spread COVID-19 in settings outside households. This finding was in consistence with previous reports of pediatric and adolescent COVID-19 cases in Ireland and Singapore which described their minimal capacity to transmit the virus at schools (15,16).
Notably, the risk of generating secondary cases among children and adolescents appears to be significantly different between influenza and COVID-19. During the 2009 H1N1 pandemic, the relative risk of pediatric and adolescent cases transmitting the virus in households was highest among those aged between 6 and 10 years (5). However, in this study, the proportion of cases that generated secondary cases was lowest among infants and young children and it was higher in those in primary schools. Furthermore, the proportion was distinctively higher among junior high school (13-15 years old) and high school children (16-18 years old), which was significantly higher than primary school children (7-12 years old). The proportions were also higher among students in professional colleges and universities and workers than primary school children, although there was no statistical significance.
The limitations of this study include a high proportion of pediatric and adolescent cases with unspecified backgrounds, potential inaccuracy in defining primary and secondary cases based on comparison of onset/confirmation dates, and limited information about contribution of control measures on transmission dynamics (13). In addition, due to the high proportion of mild and asymptomatic cases among children and adolescents with COVID-19, it could not be ruled out that the incidence of pediatric and adolescent cases was potentially underestimated.
In conclusion, this study highlighted the limited public health impact of children and adolescents in spreading COVID-19 in settings outside households, especially among those younger than junior high school children. Careful observations are required to elucidate the effectiveness of the traditional mitigation measures (e.g., school closures) to suppress COVID-19 transmissions related to children and adolescents. Further studies are required to reveal the underlying mechanisms (e.g., the angiotensin-converting enzyme 2 expression profiles, social activities) for such limited roles of children and adolescents in the COVID-19 transmission dynamics in the community.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
TadI was the principal investigator. TadI, MSu, MSa, YK, TakI, KO, HA, and HO designed the study. RM, ES, NT, and KN collected the data. TadI, YF, YK, IY, and HO analyzed the data. TadI, MSa, and HO wrote the manuscript. All authors contributed to the article and approved the submitted version.