Abstract
We estimate the distribution of serial intervals for 468 confirmed cases of COVID-19 reported in 93 Chinese cities by February 8, 2020. The mean and standard deviation are 3.96 (95% CI 3.53–4.39) and 4.75 (95% CI 4.46–5.07) days, respectively, with 12.6% of reports indicating pre-symptomatic transmission.
Keywords: Wuhan, coronavirus, epidemiology, serial interval
One sentence summary
We estimate the distribution of serial intervals for 468 confirmed cases of COVID-19 reported in 93 Chinese cities by February 8, 2020.
A new coronavirus (COVID-19) emerged in Wuhan, China in late 2019 and was declared a public health emergency of international concern by the World Health Organization (WHO) on January 30, 2020 (1). As of February 19, 2020, the WHO has reported over 75,204 COVID-19 infections and over 2,009 COVID-19 deaths (2), while key aspects of the transmission dynamics of COVID-19 remain unclear (3). The serial interval of COVID-19 is defined as the time duration between a primary case (infector) developing symptoms and secondary case (infectee) developing symptoms (4,5). Obtaining robust estimates for the distribution of COVID-19 serial intervals is a critical input for determining the reproduction number which can indicate the extent of interventions required to control an epidemic (6). However, this quantity cannot be inferred from daily case count data alone (7).
To obtain reliable estimates of the serial interval, we obtained data on 468 COVID-19 transmission events reported in mainland China outside of Hubei Province between January 21, 2020, and February 8, 2020. Each report consists of a probable date of symptom onset for both the infector and infectee as well as the probable locations of infection for both cases.
The data include only confirmed cases that were compiled from online reports from 18 provincial centers for disease control and prevention (Table S3).
Notably, 59 of the 468 reports indicate that the infectee developed symptoms earlier than the infector. Thus, pre-symptomatic transmission may be occurring, i.e., infected persons may be infectious before their symptoms appear. In light of these negative-valued serial intervals, we find that COVID-19 serial intervals better resemble a normal distribution than more commonly assumed gamma or Weibull distributions (8,9) that are limited to strictly positive values (see Supplement). We estimate a mean serial interval for COVID-19 of 3.96 [95% CI 3.53–4.39] with a standard deviation of 4.75 [95% CI 4.46–5.07], which is considerably lower than reported mean serial intervals of 8.4 days for SARS (9) and 12.6 days (10) - 14.6 days (11) for MERS. The mean serial interval is slightly but not significantly longer when the index case is imported (4.06 days [95% CI 3.55–4.57]) versus locally infected (3.66 days [95% CI 2.84–4.47]); it is slightly shorter when the secondary transmission occurs within a household (4.03 days [95% CI 3.12–4.94]) versus outside of the household (4.56 days [95% CI: 3.85–5.27]). Combining these findings with published estimates for the early exponential growth rate COVID-19 in Wuhan (12,13), we estimate a basic reproduction number (R0) of 1.32 [95% CI 1.16–1.48] (6), which is lower than published estimates that assume a mean serial interval exceeding seven days (13–15).
These estimates reflect reported symptom onset dates for 752 cases from 93 Chinese cities, who range in age from 1 to 90 years (mean 45.2 years and SD 17.21 years). Recent analysis of COVID-19 case data from mainland China, Taiwan, Hong Kong, Vietnam, South Korea, Germany and Singapore have reported average serial intervals of 7.5 days [95% CI 5.3–19] (13), 4.4 days [95% CI 2.9–6.7] (16) and 4.0 days [95% CrI 3.1–4.9] (17) based on considerably smaller samples of 6, 21 and 28 infector-infected pairs, respectively. Whereas none of these studies report negative serial intervals in which the infectee developed symptoms prior to the infector, 12.6% of the serial intervals in our sample are negative.
We note four potential sources of bias in our estimates, three of which are likely to cause underestimation of COVID-19 serial intervals. First, the data are restricted to online reports of confirmed cases and therefore may be biased towards more severe cases in areas with a high-functioning healthcare and public health infrastructure. The rapid isolation such cases may have prevented longer serial intervals, potentially shifting our estimate downwards compared to serial intervals that might be observed in an uncontrolled epidemic. Second, the distribution of serial intervals varies throughout an epidemic, with the time between successive cases contracting around the epidemic peak (18). To provide intuition, a susceptible person is likely to become infected more quickly if they are surrounded by two infected people rather than just one. Since our estimates are based primarily on transmission events reported during the early stages of outbreaks, we do not explicitly account for such compression and interpret the estimates as basic serial intervals at the outset of an epidemic. However, if some of the reported infections occurred amidst growing clusters of cases, then our estimates may reflect effective (compressed) serial intervals that would be expected during a period of epidemic growth. Third, the identity of each infector and the timing of symptom onset were presumably based on individual recollection of past events. If recall accuracy is impeded by time or trauma, cases may be more likely to attribute infection to recent encounters (short serial intervals) over past encounters (longer serial intervals). In contrast, the reported serial intervals may be biased upwards by travel-related delays in transmission from primary cases that were infected in Wuhan or another city before returning home. If their infectious period started while still traveling, then we may be unlikely to observe early transmission events with shorter serial intervals. Indeed, the mean serial interval is slightly higher for the 218 of 301 unique infectors reported to be imported cases.
Given the heterogeneity in type and reliability of these sources, we caution that our findings should be interpreted as working hypotheses regarding the infectiousness of COVID-19 requiring further validation as more data become available. The potential implications for COVID-19 control are mixed. While our lower estimates for R0 suggest easier containment, the large number of reported asymptomatic transmission events is concerning.
Supplementary Material
Acknowledgments
We acknowledge the financial support from NIH (U01 GM087719) and the National Natural Science Foundation of China (61773091).
Author Bio
Dr. Du is a postdoctoral researcher in the Department of Integrative Biology at the University of Texas at Austin. He develops mathematical models to elucidate the transmission dynamics, surveillance, and control of infectious diseases.
References
- 1.WHO | Pneumonia of unknown cause – China. 2020. January 30 [cited 2020 Feb 18]; Available from: https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/
- 2.Organization WH, et al. Coronavirus disease 2019 (COVID-19): situation report, 30. 2020; Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200219-sitrep-30-covid-19.pdf?sfvrsn=6e50645_2
- 3.Cowling BJ, Leung GM. Epidemiological research priorities for public health control of the ongoing global novel coronavirus (2019-nCoV) outbreak. Euro Surveill [Internet]. 2020. February 13; Available from: 10.2807/1560-7917.ES.2020.25.6.2000110 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Giesecke J. Modern infectious disease epidemiology. CRC Press; 2017. [Google Scholar]
- 5.Svensson A. A note on generation times in epidemic models. Math Biosci. 2007. July;208(1):300–11. [DOI] [PubMed] [Google Scholar]
- 6.Wallinga J, Lipsitch M. How generation intervals shape the relationship between growth rates and reproductive numbers. Proc Biol Sci. 2007. February 22;274(1609):599–604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Vink MA, Bootsma MCJ, Wallinga J. Serial Intervals of Respiratory Infectious Diseases: A Systematic Review and Analysis [Internet]. Vol. 180, American Journal of Epidemiology. 2014. p. 865–75. Available from: 10.1093/aje/kwu209 [DOI] [PubMed] [Google Scholar]
- 8.Kuk AYC, Ma S. The estimation of SARS incubation distribution from serial interval data using a convolution likelihood. Stat Med. 2005. August 30;24(16):2525–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lipsitch M, Cohen T, Cooper B, Robins JM, Ma S, James L, et al. Transmission dynamics and control of severe acute respiratory syndrome. Science. 2003. June 20;300(5627):1966–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cowling BJ, Park M, Fang VJ, Wu P, Leung GM, Wu JT. Preliminary epidemiological assessment of MERS-CoV outbreak in South Korea, May to June 2015 [Internet]. Vol. 20, Eurosurveillance. 2015. Available from: 10.2807/1560-7917.es2015.20.25.21163 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Park SH, Kim Y-S, Jung Y, Choi SY, Cho N-H, Jeong HW, et al. Outbreaks of Middle East Respiratory Syndrome in Two Hospitals Initiated by a Single Patient in Daejeon, South Korea. Infect Chemother. 2016. June;48(2):99–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jung S-M, Akhmetzhanov AR, Hayashi K, Linton NM, Yang Y, Yuan B, et al. Real time estimation of the risk of death from novel coronavirus (2019-nCoV) infection: Inference using exported cases [Internet]. Available from: 10.1101/2020.01.29.20019547 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med [Internet]. January 29; Available from: 10.1056/NEJMoa2001316 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Tuite AR, Fisman DN. Reporting, Epidemic Growth, and Reproduction Numbers for the 2019 Novel Coronavirus (2019-nCoV) Epidemic [Internet]. Annals of Internal Medicine. 2020. Available from: 10.7326/m20-0358 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet [Internet]. 2020. January 31; Available from: 10.1016/S0140-6736(20)30260-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zhao S, Gao D, Zhuang Z, Chong M, Cai Y, Ran J, et al. Estimating the serial interval of the novel coronavirus disease (COVID-19): A statistical analysis using the public data in Hong Kong from January 16 to February 15, 2020. medRxiv [Internet]. 2020; Available from: https://www.medrxiv.org/content/10.1101/2020.02.21.20026559v1.abstract [Google Scholar]
- 17.Nishiura H, Linton NM, Akhmetzhanov AR. Serial interval of novel coronavirus (2019-nCoV) infections [Internet]. Infectious Diseases (except HIV/AIDS). medRxiv; 2020. Available from: https://www.medrxiv.org/content/10.1101/2020.02.03.20019497v1.abstract [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Kenah E, Lipsitch M, Robins JM. Generation interval contraction and epidemic data analysis. Math Biosci. 2008. May;213(1):71–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Fit probability distribution object to data - MATLAB fitdist [Internet]. [cited 2020 Feb 19]. Available from: https://www.mathworks.com/help/stats/fitdist.html
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