Epidemiological Characteristics of Imported COVID-19 Cases, March to December 2020, Chengdu, China: Implication for Quarantine and Isolation of International Travelers

International �ights have accelerated the global spread of Coronavirus Disease 2019 (COVID-19). Determination of the optimal quarantine period for international travelers is crucial to prevent the local spread caused by imported COVID-19 cases. We performed a retrospective epidemiological study using 491 imported COVID-19 cases in Chengdu, China, to describe the characteristic of the cases and estimate the time from arrival to con�rmation for international travelers using nonparametric survival methods. Among the 491 imported COVID-19 cases, 194 (39.5%) were asymptomatic infections. The mean age was 35.6 years (SD=12.1 years) and 83.3% were men. The majority (74.1%) were screened positive for SARS-CoV-2, conducted by Chengdu Customs District, the People’s Republic of China. Asymptomatic cases were younger than presymptomatic or symptomatic cases (P<0.01). The daily number of imported COVID-19 cases displayed jagged changes. 95% of COVID-19 cases were con�rmed by PT-PCR within 14 days (95% CI: 13-15) after arriving in Chengdu. A 14-day quarantine measure can ensure non-infection among international travelers with a 95% probability. Policymakers may consider an extension of the quarantine period to minimize the negative consequences of the COVID-19 con�nement and prevent the international spread of COVID-19. Nevertheless, the government should consider the balance between COVID-19 and socioeconomic development, which may cause more serious social and health crises.


Introduction
Coronavirus Disease 2019 (COVID- 19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected hundreds of millions of people and caused millions of deaths globally 1 .
International ights provide the opportunity for the global spread of COVID-19 2 .In Africa, air tra c is signi cantly associated with COVID-19 morbidity and mortality, and plays an important role in the geographical spread of the disease 3 .Travel restriction and travel quarantine have helped mitigate the international spread of COVID-19 2,4,5 .
The quarantine duration was determined by the incubation period, the time from exposure to an infectious disease to the onset of symptoms.Theoretically, it's preferable to quarantine international travelers for a longer period than the maximum incubation period since the person-to-person transmission prior to symptom onset [6][7][8][9] .The estimated length of the incubation period of COVID-19 varies across the disease severity, model methods, and sample sizes [10][11][12][13][14][15][16][17][18][19][20][21] .Thus, the optimal quarantine duration for COVID-19 needs to be assessed using the previously reported incubation period.Furthermore, a quarantine period varies all over the world.It is unclear whether the 14-day quarantine is su cient to protect against the international spread of COVID-19.In this study, we provide direct estimates of the optimal quarantine period for international travelers, based on the interval between the date of arrival and the date of con rmation of imported COVID-19 cases in Chengdu, China.We also evaluate the effectiveness of Customs screening at detecting international travelers infected with SARS-CoV-2.

Time to con rmation
The cumulative distribution of time to con rmation, de ned as the time between the date of arriving in Chengdu and the date of con rmation of COVID-19 by PT-PCR, is shown in Figure 2.Among 491 cases, 95% were con rmed by PT-PCR within 14 days (95% CI: 13-15) after arriving in Chengdu.For different stages of infections (Figure 3 A), 95% of asymptomatic cases were con rmed by PT-PCR within 15 days (13-16) after arrival, 95% of presymptomatic cases were con rmed by PT-PCR within 13 days (13-13) after arrival, 95% of symptomatic cases were con rmed by PT-PCR within 14 days (13-17) after arrival.Furthermore, 95% of male cases were con rmed by PT-PCR within 14 days (13-15) after arrival, 95% of female cases were con rmed by PT-PCR within 14 days (12-16) after arrival (Figure 3B).

Discussion
This analysis of imported COVID-19 cases in Chengdu, China, provides insight into formulating a rationale for determining the optimal quarantine period for international travelers.The values estimated provide the evidentiary foundation for containing the international spread of COVID-19.Analyses of the interval between the date of arrival and the date of con rmation of imported COVID-19 cases revealed that at least 5% of incubation periods could be longer than 14 days.These results paint a positive picture of the impact of obligatory household quarantine for 14 days in Chengdu.Public health authorities may consider a slight extension of the quarantine period to deal with uncertainty in the incubation periods.
All ages of the population are susceptible to SARS-CoV-2 infection, younger adults who contracted SARS-CoV-2 are more likely to be asymptomatic or have mild diseases [22][23][24] .We found that asymptomatic cases were younger than presymptomatic or symptomatic cases.The age-dependent T-cell and B-cell dysfunction and differential expression of in ammatory genes could lead to immune dysregulation and induce more prolonged proin ammatory responses, potentially contributing to poor outcomes [25][26][27] .
This work further supports a high prevalence of asymptomatic cases in SARS-CoV-2 infections 28,29 .39.5% of international travelers infected with SARS-CoV-2 remains asymptomatic, which is lower than the range reported for SARS-CoV-2 (40%-45%) 29 .Asymptomatic international travelers will be missed by symptom-based surveillance 30 , even if screened for SARS-CoV-2, so it is crucial to implement the travel quarantine for international travelers during the COVID-19 pandemic.
Our estimation of the 95th quantile of the interval between the date of arrival and the date of con rmation, 14 days, supports the adopted mandatory quarantine period of 14 days in China 19 .Of note, we estimated that about 5.0% of imported COVID-19 cases would not have a positive SARS-CoV-2 RT-PCR array until 14 days after arriving in Chengdu.Similarly, previous work had suggested that at least 5% of cases would take 14 days or more to develop symptoms [19][20][21] .In particular, asymptomatic cases can transmit SARS-CoV-2 to others for longer than 14 days 29 .It has appeared several COVID-19 outbreaks in China due to international imported COVID-19 cases 31 .Consequently, the 14-day household quarantine was recommended to international travelers discharged from a designated centralized quarantine site for 14 days in Chengdu.
Our study has several limitations.First, international travelers arriving in Chengdu might be a biased sample due to the airline control measures implemented by the Civil Aviation Administration of China.Second, we could not estimate the incubation period distribution of imported COVID-19 cases since the possible exposure time of imported COVID-19 cases was not available.Moreover, a minority of international travelers who arrived in December 2020 received COVID-19 vaccines, so we could not evaluate the impact of the vaccines.Although vaccination is effective and safe against COVID-19 32,33 , the vaccinated population may contract SARS-CoV-2 and infect others [34][35][36] .Finally, we could not assess the true transmissibility of imported cases with an extended incubation period, longer than 14 days.A longitudinal study should be carried out to investigate the infectious period of COVID-19 or how long infected individuals remain infectious to others, which is associated with release from quarantine.

Conclusions
The high prevalence of asymptomatic infection and the long incubation period have made it challenging to contain the COVID-19 pandemic.To ensure non-infection with a 95% probability, public health authorities should quarantine international travelers for more than 14 days.Also, policymakers may consider an obligatory household quarantine or household health monitoring after a 14-day designated centralized quarantine, to minimize the negative consequences of the COVID-19 con nement and prevent the international spread of COVID-19.Nevertheless, the government should consider the balance between COVID-19 and socioeconomic development, which may cause more serious social and health crises.

Source of data
A retrospective observational study of the imported laboratory-con rmed COVID-19 cases from March 2020 to December 2020 was performed.All international travelers, arriving in Chengdu, should be screened for SARS-CoV- Regardless of symptoms, all international travelers should comply with a centralized isolated medical quarantine for 14 days and household quarantine for 14 days in Chengdu.Basic demographic information and time from arrival to con rmation by RT-PCR were recorded for all con rmed cases.We excluded 2 imported COVID-19 cases who received a centralized isolated medical quarantine in the other city, subsequently arrived in Chengdu, and were con rmed by RT-PCR.Hence, we included 491 cases in the study.

Case de nitions
COVID-19 cases were divided into asymptomatic, presymptomatic, and symptomatic cases.Asymptomatic cases were de ned as being con rmed by RT-PCR without any symptoms.
Presymptomatic cases were de ned as being con rmed by RT-PCR, prior to the onset of symptoms.Symptomatic cases were de ned as being con rmed by RT-PCR and the development of symptoms.

Time to con rmation
In this study, "time to con rmation" was de ned as the interval in days between the date of arriving in Chengdu and the date of con rmation of COVID-19 by PT-PCR.Time between arrival in Chengdu and SARS-CoV-2 con rmation.We estimated that 95% of cases were con rmed by PT-PCR within 14 days (95% CI: 13-15) after arriving in Chengdu.

Figures
Figures

Table 1
Data are mean ± standard deviation or n (%).†Compared with presymptomatic or symptomatic cases, P<0.01, adjusted using the Bonferroni correction.‡Fisher's exact test.
Data are mean ± standard deviation or n (%).†Compared with presymptomatic or symptomatic cases, P<0.01, adjusted using the Bonferroni correction.‡Fisher'sexact test.Progression of the imported COVID-19 epidemic in Chengdu correlated with airline control measures implemented by the Civil Aviation Administration of China.Flight plans adjustment that each foreign airline would be only allowed to maintain one route to China with no more than one weekly ight was implemented as of March 29, 2020.International routines decreased, and imported COVID-19 cases decreased.Incentives and circuit breaker measures for ights have been implemented since June 8, 2020.
2, shortly conducted by Chengdu Customs District, the People's Republic of China.Con rmations of COVID-19 cases were done at the Chengdu Center for Disease Control and Prevention, using reverse transcription polymerase chain reaction (RT-PCR) assays targeting two different regions of the RdRp gene in SARS-CoV-2.All methods were carried out in accordance with relevant guidelines.All experiments were carried out in the Laboratory of Chengdu Center for Disease Control and Prevention.
Data collection was determined by the Article 7, 12, 48, Law of the People's Republic of China on Prevention and Treatment of Infectious Diseases to be part of the epidemiological investigation of a noti able infectious disease and therefore the individual informed consent was waived.Partial data was available from the o cial website of Chengdu Municipal Health Commission (http://cdwjw.chengdu.gov.cn/cdwjw/c135632/yqbd.shtml).Paragraph 1 of Article 12: units and individuals within the territory of the people's Republic of China must accept the investigation, inspection, sample collection, isolation treatment and other prevention and control measures associated with infectious diseases by Center for Disease Control and Prevention and medical institutions, and truthfully provide relevant information.Center for Disease Control and Prevention and medical institutions shall not disclose relevant information and materials involving personal privacy.Paragraph 1 of Article 48: When an epidemic of infectious diseases occurs, Center for Disease Control and Prevention and other professional and technical institutions related to infectious diseases designated by the Administrative Department of Health of the People's Government at or above the provincial level may enter the epidemic focus and epidemic area of infectious diseases for investigation, sample collection, technical analysis and testing.