key: cord-0927836-uh22jgo7
authors: Ma, Xiaowei; Wu, Keyi; Li, Yongguang; Li, Shunming; Cao, Lan; Xie, Huaping; Zheng, Jiazhen; Zhou, Rui; Yuan, Zelin; Huang, Zhiwei; Yuan, Jun; Wu, Xianbo
title: Contact tracing period and epidemiological characteristics of an outbreak by SARS-CoV-2 Delta variant in Guangzhou
date: 2022-01-29
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2022.01.034
sha: 1bbf471d084996bec7b2f2f88bf0566d5360b3db
doc_id: 927836
cord_uid: uh22jgo7

Objectives : An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant occurred in Guangzhou in 2021. This study aimed to identify the transmission dynamics and epidemiological characteristics of the Delta variant outbreak to formulate an effective prevention strategy. Methods : A total of 13102 close contacts and 69 index cases were collected. The incubation period, serial interval, and time interval from the exposure of close contacts to the symptom onset of cases were estimated. Transmission risks based on exposure time and various characteristics were also assessed. Results : The mean time from exposure to symptom onset among non-household pre-symptomatic transmission was 3.83 ± 2.29 days, the incubation period was 5 days, and the serial interval was 3 days. The secondary attack rate was high within 4 days before onset and 4–10 days after symptom onset. Compared with other contact types, household contact had higher transmission risk. The transmission risk increased with the number and frequency of contact with index cases. Cycle threshold (Ct) values were associated with lower transmission risk (adjusted odds ratio [OR] 0.93 [95% CI 0.88–0.99] for ORF 1ab gene; adjusted OR 0.91 [95% CI 0.86–0.97] for N gene). Conclusion : The contact tracing period may need to be extended to 4 days before symptom onset. The Ct value of index cases, the number and frequency of contact with index cases, and household contact were associated with higher transmission risk of SARS-CoV-2 Delta.

Since the B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 Running title: Epidemiological characteristics of COVID-19 outbreak 5 (SARS-CoV-2) was first identified in India in October 2020, it has become the main epidemic strain in many countries (Alizon et al., 2021; Del et al., 2021; Lauring and Malani, 2021; Lopez et al., 2021) . As of September 21, 2021, the variant had spread to 185 countries and regions (WHO, 2021) . The Delta variant has increased transmissibility because of its increased fitness, and it could be able to escape from host immunity (Hoffmann et al., 2021; Planas et al., 2021) . Thus, it poses a great threat to global public health.

Contact tracing and isolation of confirmed and suspected cases are crucial measures to control infectious diseases (Liu et al., 2020) , and have been implemented in the prevention of coronavirus disease 2019 . However, these measures will become less effective if the reproduction number is high or if infectiousness occur in the presymptomatic period (Hellewell et al., 2020) . A study using mathematical modelling demonstrated that in higher transmission scenarios, tracing and isolating a larger proportion of close contacts are needed to bring the median effective reproductive number below 1 and therefore prevent the transmission of COVID-19 (Hellewell et al., 2020) . Compared with the wild-type virus, the Delta variant has higher transmissibility.

The basic reproduction number and viral load in a person infected with the Delta variant are higher than those of the wild-type virus (Luo et al., 2021; Liu and Rocklov, 2021) .

This finding indicates that a higher level of contact tracing may be needed to contain the transmission of the Delta variant.

The presymptomatic transmission of COVID-19 has been found in previous studies (Liu et al., 2020; Huang et al., 2020; Ren et al., 2021) , and some studies indicated that the proportion of the presymptomatic transmission of the Delta variant is higher than those of other variants (Min et al., 2021; Zhang et al., 2021) . Tracing the contacts of confirmed cases and testing (and isolating) the contacts before symptom Running title: Epidemiological characteristics of COVID-19 outbreak 6 onset are the only way to prevent disease transmission (Hellewell et al., 2020) . Therefore, effectively searching and isolating contacts before the infected cases show symptoms are extremely important in the prevention of the Delta variant.

In China, according to "The New Coronavirus Pneumonia Prevention and Control Plan (Eighth Edition)," close contacts are defined as those who had contact, without effective protective measures (such as without wearing proper personal protection equipment), with suspected and confirmed cases within 2 days before the onset of symptoms or within 2 days before the sampling of asymptomatic infected persons (China State Council, 2021) . Tracing close contacts according to the scale of this definition was able to control the spread of COVID-19 caused by wild-type SARS-CoV-2 (Lai et al., 2020) . Nevertheless, the criteria of contact tracing may need to be more inclusive (such as expanding contact tracing to a longer time frame) for the prevention of variants with higher transmissibility, such as the Delta variant. On May 21, 2021, a local case of the Delta variant was detected in Guangzhou, China. It then caused a local outbreak in the following days and weeks. This epidemic provides an opportunity to estimate transmission parameters, such as the incubation period and serial interval of the epidemic, as well as the transmission dynamics among the close contacts of index cases infected with the Delta variant. Other epidemical characteristics of the Delta variant can also be observed. Cycle threshold (Ct) value is an important indicator when studying the epidemical characteristics of COVID-19, as it may be associated with mortality (Huang et al., 2020) , disease severity (Liu et al., 2021; Liu et al., 2020; Zheng et al., 2020) , and biochemical and hematological markers (Azzi et al., 2020; Liu et al., 2020; Shi et al., 2020) . However, whether Ct values will affect the transmission risk of the Delta variant is still unclear.

Running title: Epidemiological characteristics of In this study, we aimed to investigate the epidemiological characteristics and transmission dynamics of COVID-19 caused by the Delta variant. We also evaluated the transmission risk by different exposure windows and various characteristics.

Since the first local case was confirmed in Liwan District of Guangzhou City on May 21, 2021 the Guangzhou Center for Disease Control and Prevention (CDC) immediately carried out case searches and strengthened disease surveillance. Index cases were detected through screening in fever clinics, tracing and screening of close contacts, and community screening. Nasopharyngeal swabs were collected for reverse transcription polymerase chain reaction (RT-PCR) test to quickly screen out suspected cases. The PCR-positive samples were sent to Guangzhou CDC for review, and those confirmed to have a positive PCR result were sent to designated hospitals for diagnosis, isolation, and treatment. All the close contacts were identified and quarantined according to the epidemiology investigations of confirmed cases and big data technology screening through multisectoral collaboration.

From May 21 to June 18, 2021 69 index cases and 13102 close contacts were identified by Guangzhou CDC. The index cases and close contacts were people living in Guangzhou during the epidemic period. The information of index cases included demographic characteristics, epidemiological history, and clinical data. Close contacts were quarantined for 14 days from last contact with index cases and were subjected to regular PCR testing and physical condition monitoring.

Running title: Epidemiological characteristics of COVID-19 outbreak 8 The incubation period and serial interval of the COVID-19 epidemic caused by the Delta variant were estimated to investigate its epidemiological features. Incubation period is defined as the time from exposure to symptom onset. For asymptomatic cases, incubation period is the time between exposure and the first PCR-positive test result.

We excluded cases of household contact because their exposure time was difficult to determine. As a result, 65 cases were included in the estimation of incubation period.

Serial interval is defined as the period of time from the onset of symptoms in the infector (i.e., index case) to the onset of symptoms in an associated infectee (i.e., close contact). For asymptomatic cases, serial interval is the time difference between the first PCR-positive test of the infector and infectee. Thirty-five non-household infectorinfectee pairs to investigate the epidemiological characteristics of presymptomatic transmission. Each infectee was the earliest confirmed cases among close contacts exposed to the infectors in the presymptomatic period. Then, the time period between the exposure of infectees and the symptom onset of infectors was estimated. For symptomatic index cases, the time interval from the exposure of infected cases to symptom onset was used. For asymptomatic index cases, the time interval from the exposure of infectees to the first positive PCR test was used.

The relationships between index cases and close contacts were divided into five contact types: household (family or living together), dine together, socially interacting (including colleagues, classmates, and those who had relationship and interaction), casual contact (including public places, community contact, and those who had no relationship and interaction), and multiple types (more than one contact type). Contact frequency was categorized as "occasional," "moderate," and "often." 

The main outcome was transmission, which means that a confirmed infection appeared among close contacts under quarantine. Secondary attack rate is defined as the ratio of the number of confirmed cases among the close contacts. Asymptomatic cases are those who had no relevant clinical symptoms but had a positive etiological test result of respiratory specimen. Symptomatic confirmed cases were classified into mild, moderate, severe, and critical according to the "COVID-19 diagnosis and treatment protocol." Details are shown in Supplementary text. Vaccination status was categorized as unvaccinated, vaccinated with one dose, and vaccinated with two doses. Close contacts need to be paired with their indicator cases to analyze the relationship between the Ct values of index cases and disease transmission. Therefore, the close contacts linked to only one index case were selected for analysis.

Incubation period, serial interval and time period from exposure to symptom were estimated using the data obtained from epidemiological investigations. The median Ct values of the first positive PCR test of the ORF 1ab and N genes were separately We compared the secondary attack rate using chi-square test and used multivariable logistic regression models to estimate transmission risk using the characteristics of close contacts (age, sex, number of index cases, contact types, and frequency) and the time of exposure (using non-household contacts linked to only one index case). We also explored the association between the transmission risk of close contacts and the Ct values of index cases, as well as between vaccination status and Ct values. The missing data of covariates were imputed using multiple imputation with chained equations. All analysis were performed by STATA 15.0 with two-sided P < 0.05 as statistically significant.

The data in this study were obtained from a work for preventing and controlling the COVID-19 outbreak by Guangzhou CDC as required by the public health policy of the National Health Commission of China. According to the law on the prevention and control of infectious diseases, cases should truthfully provide their relevant information.

Hence, individual informed consent was waived, and after consultation with the ethics committee of Guangzhou CDC, this study was considered that ethical approval is not required. The analytical datasets were constructed anonymously.

A total of 69 index cases and 13102 close contacts in Guangzhou were collected.

Among the 13102 contacts, 84 developed secondary cases. Therefore,153 cases were found in this epidemic. Table 1 shows the demographic and epidemiological characteristics of all close contacts. Of the 13102 close contacts, 1.62% were household contacts, 20.57% were socially interacting, and 54.08% were casual contact. The median time from the exposure to symptom onset of index cases was −1 day, and most of the close contacts were exposed to index cases before the symptom onset of cases.

The median age of index cases was 51 years (IQR 32-67), and the median age of the secondary cases was 46 years (IQR 24-68). Most of the cases were males, most of whom had not been vaccinated and often wore masks when going out. Of the 153 cases, 11 (7.19%) were asymptomatic, and the majority of symptomatic cases presented mild and moderate symptoms with fever and dry cough as the main symptoms (Table A.1).

The median incubation period for all cases was 5 days (IQR 3-7), and the median serial interval was 3 days (IQR 1-5). The mean time from exposure to symptom onset among pre-symptomatic transmission was 3.83 ± 2.29 days (95% CI 3.04-4.62).

The median Ct values of the first positive PCR test was 26.50 (IQR 21.33-33.44) for the ORF 1ab gene and 25.50 (IQR 19.87-32.00) for the N gene, respectively.

The total secondary attack rate was 0.64% (95% CI 0.51%-0.80%). Contacts aged < 20 years (1.07% [95% CI 0.63%-1.77%]) and ≥60 years (1.39% [95% CI 0.95%-2.02%]) had higher secondary attack rates than those aged 20-50 years (0.41% [95% CI 0.30%-0.57%]). Compared with the close contacts whose exposure to the index case was 10 days after symptom onset (zero transmission of 200 contacts [95% CI 0.00%-2.35%]), those who were exposed 4 days before symptom onset (0.37% [95% CI 0.23%-0.59%]) and 4-10 days after symptom onset (4-6 days: 0.41% [95% CI 0.07%-1.64%] and 7-10 days: 0.25% [95% CI 0.04%-1.00%]) had higher secondary attack rates. In multivariable logistic models, females were more likely to be secondary cases than males (adjusted OR 1.79, 95% CI 1.14-2.84). The transmission risk increased with the number (1: adjusted OR, 3.00 [95% CI 1.62-5.52] to ≥ 3: adjusted Table 3 ). The Ct values of the N gene were higher in those who received two doses of vaccine after adjusting for age and sex ( Table A. 2).

In the present study, we found that the median incubation period and serial interval were 5 and 3 days, respectively. The mean time from exposure to symptoms onset was 3.83 days among presymptomatic transmission cases. A higher secondary attack rate was found within 4 days before and 4-10 days after symptom onset, followed by a lower secondary rate at over 10 days after symptom onset. In terms of the risk factors for transmission, a higher Ct value in index cases was associated with a lower risk of SARS-CoV-2 transmission. Compared with other contact types, household contact had higher infection risk. Close contacts exposed to a higher number of index cases and with a higher frequency of contact were more likely to be infected.

In the prevention of COVID-19, presymptomatic transmission would hinder the effectiveness of control measures. Tracing the contacts of infected cases after symptomatic onset is relatively easier compared with contacts in the presymptomatic period, because presymptomatic transmission is hidden, and the onset time of infectiousness of cases is uncertain. Without sufficient contact tracing, those omitted Running title: Epidemiological characteristics of COVID-19 outbreak 13 contacts will then become a challenge in controlling the COVID-19 epidemic. In this study, the median serial interval (3 days) was shorter than the incubation period (5 days), which indicates that presymptomatic transmission is likely to have occurred and may even be more frequent than symptomatic transmission (Nishiura et al., 2020) . The earliest presymptomatic transmission occurred 9 days before the symptom onset of the index case, and the average time of presymptomatic transmission was 3.83 days before the symptom onset of the index case. Moreover, the secondary attack rate was relatively high among those whose initial exposure to the index case was within 4 days before and 10 days after the symptom onset of index cases. This finding implies that presymptomatic transmission in this epidemic may reduce the effect of contact tracing based on the current criteria of close contacts. Actually, screening close contacts according to the current definition of close contacts has failed to contain the epidemic.

The epidemic was finally effectively controlled by extending the screening time of close contacts to 4 days before the onset of the case tentatively, social distancing and community closure management in high-risk areas, and actively finding cases and close contacts through mass testing. The results suggest that expanding the time scale of contact tracing and taking more active actions to detect the contacts of infected persons before they develop symptoms can improve the effectiveness of control measures against the Delta variant.

Transmission and viral shedding before COVID-19 symptom onset were observed in previous studies (Jefferson et al., 2021; Cheng et al., 2020; Ge et al., 2021; He et al., 2020) . High transmission risk and viral load were found around the time of symptom onset (between about −2 and 3 days from symptom onset) (Cheng et al., 2020; Ge et al., 2021) . In the present study, the secondary attack rate was high from 4 days to at least 4 days before illness onset (Min et al., 2021) . This finding suggest that the Delta variant may have transmissibility in an earlier period than the wild-type virus. Viral dynamics studies showed that the viral load decreased gradually within 7 days of symptom onset (He et al., 2020; Zou et al., 2020) . A contact tracing study in Taiwan found that the risk of transmission declined after 1 week of symptom onset (Cheng et al., 2020) . However, we observed in the study that transmission declined 10 days after the onset of symptoms, which indicates that the Delta variant may have longer infection duration. This finding was supported by another study, which found a prolonged viral shedding of the Delta variant than the wild-type virus (Wang et al., 2021) . Therefore, extending the contact tracing period to perhaps 4 days before symptom onset and strengthening the management of infected cases may be necessary.

Our results showed that the increased Ct values of index cases was associated with a lower transmission risk. The Ct value is an inversely proportional measure of viral load in the specimen (Trunfio et al., 2021) . Thus, a lower viral load is associated with a lower transmission risk, which was consistent with a previous study (Marks et al., 2021) . Compared with the 2020 epidemic, the Ct values of first positive PCR test were lower (34.31, IQR 31.00-36.00 for ORF 1ab gene) (Li et al., 2021) , which suggests that the viral load of the Delta variant was higher than that of the wild-type virus in infectious people. The peak viral load of the Delta variant is also higher than that of the wild-type virus (Wang et al., 2021) . Therefore, the high viral load seems to contribute to the increased transmissibility of the Delta variant.

The secondary attack rate of COVID-19 in our study was 0.64% among all close contacts, and the secondary attack rate among household contact was similar to the secondary attack rate in the 2020 epidemic (9.26% vs. 10.30%) (Luo et al., 2020) . In this epidemic, household contact was the highest risk factor for SARS-CoV-2 Running title: Epidemiological characteristics of COVID-19 outbreak 15 transmission, which was in line with previous results (Ng et al., 2021; She et al., 2020) .

This finding implies that the prevention of family transmission remains the most important measure to control the COVID-19 epidemic. Compared with male sex, female sex was associated with higher COVID-19 transmission risk. A national study in mainland China estimated a higher attack rate of COVID-19 in females than in males, which implies that females are in more likely to be infected by SARS-CoV-2 than males (Qian et al., 2020) . A potential reason may be that females have higher angiotensinconverting enzyme 2 (ACE2) levels (Bhatia et al., 2013) , because the ACE2 gene is located in the X chromosome. Moreover, ACE2 receptor is the channel through which SARS-CoV-2 viruses enter tissues (Batlle et al., 2020) , and cause infection.

Additionally, we found that transmission risk increased with the increase in the number of index cases and frequency of exposure of the close contacts. Gathering with people outside will increase the chance of contact with suspicious cases and increase the risk of infection. Considering the higher transmissibility and faster spread of the Delta variant, case isolations and contact tracing alone would be unlikely to control the transmission of the Delta variant. Aggressive social distancing and community closure management in high-risk areas may be essential to contain the spread of the COVID-19 epidemic caused by the Delta variant.

Our study has several limitations. First, the symptom onset time of most cases was obtained retrospectively through epidemiological investigations; therefore, recall bias may occur. Second, we used Ct values as a proxy of viral load, but the precise correlation between Ct values and viral load may be influenced by many factors. Our results suggested a potential link between viral load and transmission risk. Third, we were unable to examine potential determinants for the secondary attack rate of household transmission, including the characteristics of index cases and household Running title: Epidemiological characteristics of COVID-19 outbreak 16 contacts. We were also unable to estimate the transmission risk of household contacts by the timing of exposure because the exposure time for intra-family transmissions was difficult to pinpoint. Finally, Guangzhou adopted strict prevention and control measures at the initial stage of the epidemic and carried out large-scale PCR test screening, which quickly contained the spread of the epidemic. These measures were different from other countries, and it may affect the representativeness of our results.

In conclusion, our results showed that the mean time from exposure to symptom onset of presymptomatic transmission cases was 3.83 days, and most COVID-19 cases caused by the transmission of the Delta variant occurred within 4 days before and 4-10 days after symptom onset. High Ct values were associated with low transmission risk, and household contact was at higher risk of transmission than other contact types. Close contacts exposed to a large number of index cases and with higher frequency had higher risk of being infected. The Delta variant was more transmissible, and the infectivity 

The data used in this study were obtained from a work for preventing and controlling the COVID-19 outbreak by Guangzhou CDC as required by the public health policy of the National Health Commission of China. According to the law on the prevention and control of infectious diseases, cases should truthfully provide their relevant information.

Hence, individual informed consent was waived, and after consultation with the ethics committee of Guangzhou CDC, the study was considered that ethical approval is not required. The analytical data sets were constructed anonymously.

The authors declare no conflict of interest. contacts were non-household contact those who linked to only one case. The negative value means the close contacts have exposed to the index cases before the case had symptoms. 

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These authors jointly supervised this work: Jun Yuan and Xianbo Wu.Preference for color: online only.

We thank Guangzhou CDC for providing the data and their work in the prevention and control of the COVID-19 outbreak.

This work was supported by the National Natural Science Foundation of China