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The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Feng at the Chinese Center for Dis- ease Control and Prevention, No. 155 Changbai Rd., Changping District, Bei- jing, China, or at fengzj@chinacdc.cn; to Dr. G.M. Leung or Dr. Cowling at the School of Public Health, Li Ka Shing Fac- ulty of Medicine, University of Hong Kong, 21 Sassoon Rd., Pokfulam, Hong Kong, China, or at gmleung@hku.hk or bcowling@hku.hk, respectively; or to Dr. B. Yang at the Hubei Center for Disease Control and Prevention, No. 35 Zhuodao- quan North Rd., Hongshan District, Wuhan, Hubei, China, or at 49205957@qq.com. Drs. Q. Li, X. Guan, P. Wu, and X. Wang and Drs. B. Cowling, B. Yang, M. Leung, and Z. Feng contributed equally to this article. This article was published on January 29, 2020, and last updated on January 30, 2020, at NEJM.org. DOI: 10.1056/NEJMoa Copyright © 2020 Massachusetts Medical Society.
BACKGROUND The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) oc- curred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemio- logic characteristics of NCIP.
METHODS We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number.
RESULTS Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence inter- val [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9).
CONCLUSIONS On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dy- namics apply elsewhere. Measures to prevent or reduce transmission should be imple- mented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.)
A BS TR AC T
Early Transmission Dynamics in Wuhan, China,
of Novel Coronavirus–Infected Pneumonia
Qun Li, M.Med., Xuhua Guan, Ph.D., Peng Wu, Ph.D., Xiaoye Wang, M.P.H., Lei Zhou, M.Med., Yeqing Tong, Ph.D., Ruiqi Ren, M.Med., Kathy S.M. Leung, Ph.D., Eric H.Y. Lau, Ph.D., Jessica Y. Wong, Ph.D., Xuesen Xing, Ph.D., Nijuan Xiang, M.Med., Yang Wu, M.Sc., Chao Li, M.P.H., Qi Chen, M.Sc., Dan Li, M.P.H., Tian Liu, B.Med., Jing Zhao, M.Sc., Man Liu, M.Sc., Wenxiao Tu, M.Med., Chuding Chen, M.Sc., Lianmei Jin, M.Med., Rui Yang, M.Med., Qi Wang, M.P.H., Suhua Zhou, M.Med., Rui Wang, M.D., Hui Liu, M.Med., Yingbo Luo, M.Sc., Yuan Liu, M.Med., Ge Shao, B.Med., Huan Li, M.P.H., Zhongfa Tao, M.P.H., Yang Yang, M.Med., Zhiqiang Deng, M.Med., Boxi Liu, M.P.H., Zhitao Ma, M.Med., Yanping Zhang, M.Med., Guoqing Shi, M.P.H., Tommy T.Y. Lam, Ph.D., Joseph T. Wu, Ph.D., George F. Gao, D.Phil., Benjamin J. Cowling, Ph.D., Bo Yang, M.Sc., Gabriel M. Leung, M.D., and Zijian Feng, M.Med.
Original Article
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S
ince December 2019, an increasing number of cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) have been identified in Wuhan, a large city of 11 million people in central China.1-3^ On December 29, 2019, the first 4 cases reported, all linked to the Huanan (Southern China) Seafood Wholesale Market, were identified by local hospitals using a surveillance mechanism for “pneumonia of un- known etiology” that was established in the wake of the 2003 severe acute respiratory syndrome (SARS) outbreak with the aim of allowing timely identification of novel pathogens such as 2019- nCoV.^4 In recent days, infections have been iden- tified in other Chinese cities and in more than a dozen countries around the world.^5 Here, we provide an analysis of data on the first 425 lab- oratory-confirmed cases in Wuhan to describe the epidemiologic characteristics and transmission dynamics of NCIP.
Me thods
Sources of Data The earliest cases were identified through the “pneumonia of unknown etiology” surveillance mechanism.^4 Pneumonia of unknown etiology is defined as an illness without a causative patho- gen identified that fulfills the following criteria: fever (≥38°C), radiographic evidence of pneumo- nia, low or normal white-cell count or low lym- phocyte count, and no symptomatic improvement after antimicrobial treatment for 3 to 5 days fol- lowing standard clinical guidelines. In response to the identification of pneumonia cases and in an effort to increase the sensitivity for early de- tection, we developed a tailored surveillance proto- col to identify potential cases on January 3, 2020, using the case definitions described below.^1 Once a suspected case was identified, the joint field epidemiology team comprising members from the Chinese Center for Disease Control and Pre- vention (China CDC) together with provincial, local municipal CDCs and prefecture CDCs would be informed to initiate detailed field investiga- tions and collect respiratory specimens for cen- tralized testing at the National Institute for Viral Disease Control and Prevention, China CDC, in Beijing. A joint team comprising staff from China CDC and local CDCs conducted detailed field investigations for all suspected and confirmed 2019-nCoV cases.
Data were collected onto standardized forms through interviews of infected persons, rela- tives, close contacts, and health care workers. We collected information on the dates of illness onset, visits to clinical facilities, hospitalization, and clinical outcomes. Epidemiologic data were collected through interviews and field reports. Investigators interviewed each patient with in- fection and their relatives, where necessary, to determine exposure histories during the 2 weeks before the illness onset, including the dates, times, frequency, and patterns of exposures to any wild animals, especially those purportedly available in the Huanan Seafood Wholesale Market in Wuhan, or exposures to any relevant environ- ments such as that specific market or other wet markets. Information about contact with others with similar symptoms was also included. All epidemiologic information collected during field investigations, including exposure history, time- lines of events, and close contact identification, was cross-checked with information from mul- tiple sources. Households and places known to have been visited by the patients in the 2 weeks before the onset of illness were also investigated to assess for possible animal and environmental exposures. Data were entered into a central da- tabase, in duplicate, and were verified with Epi- Data software (EpiData Association).
Case Definitions The initial working case definitions for suspected NCIP were based on the SARS and Middle East respiratory syndrome (MERS) case definitions, as recommended by the World Health Organization (WHO) in 2003 and 2012.6-8^ A suspected NCIP case was defined as a pneumonia that either fulfilled all the following four criteria — fever, with or without recorded temperature; radio- graphic evidence of pneumonia; low or normal white-cell count or low lymphocyte count; and no reduction in symptoms after antimicrobial treatment for 3 days, following standard clinical guidelines — or fulfilled the abovementioned first three criteria and had an epidemiologic link to the Huanan Seafood Wholesale Market or con- tact with other patients with similar symptoms. The epidemiologic criteria to define a suspected case were updated on January 18, 2020, once new information on identified cases became available. The criteria were the following: a travel history to Wuhan or direct contact with patients from
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cifically, the latter part of the curve does not indicate a decrease in the number of incident cases but is due to delayed case ascertainment at the cutoff date. Care should be taken in inter- preting the speed of growth in cases in January, given an increase in the availability and use of testing kits as time has progressed. The major- ity of the earliest cases included reported expo- sure to the Huanan Seafood Wholesale Market, but there was an exponential increase in the number of nonlinked cases beginning in late December. The median age of the patients was 59 years (range, 15 to 89), and 240 of the 425 patients (56%) were male. There were no cases in chil- dren below 15 years of age. We examined char- acteristics of cases in three time periods: the
first period was for patients with illness onset before January 1, which was the date the Huan- an Seafood Wholesale Market was closed; the second period was for those with onset between January 1 and January 11, which was the date when RT-PCR reagents were provided to Wuhan; and the third period was those with illness onset on or after January 12 (Table 1). The patients with earlier onset were slightly younger, more likely to be male, and much more likely to report exposure to the Huanan Seafood Wholesale Market. The proportion of cases in health care workers gradually increased across the three periods (Table 1). We examined data on exposures among 10 confirmed cases, and we estimated the mean incubation period to be 5.2 days (95% confidence
Figure 1. Onset of Illness among the First 425 Confirmed Cases of Novel Coronavirus (2019-nCoV)–Infected Pneumonia (NCIP) in Wuhan, China. The decline in incidence after January 8 is likely to be due to delays in diagnosis and laboratory confirmation. China CDC denotes Chi- nese Center for Disease Control and Prevention, NHC National Health Commission of the People’s Republic of China, PCR polymerase chain reaction, WHC Wuhan Health Commission, and WHO World Health Organization.
No. of Cases
45
50
35
40
30 25
15 10
20
5 0 27 30 3 6 9 12 15 18 21 24 27 30 2 5 8 11 14 17 20 Nov. 2019
Dec. 2020
Jan.
A novel coronavirus was officially announced as the causative pathogen of the outbreak by China CDC
Huanan Seafood Wholesale Market closed Outbreak announced by WHC; NHC and China CDC involved in investigation and response Case-finding activated Pneumonia cases linked to the Huanan Seafood Wholesale Market
China CDC publicly shared the gene sequence of the novel coronavirus; completed PCR diagnostic reagent development and testing PCR diagnostic reagents provided to Wuhan First confirmed case from Wuhan reported outside China (in Thailand) China CDC emergency response level upgraded to Level 1 (the highest level); national technical protocols for 2019- nCoV released by NHC
NCIP incorporated as a notifiable disease in the Infectious Disease Law and Health and Quarantine Law in China Reagent probes and primers shared with the public by China CDC
Strict exit screening measures activated in Wuhan, people with body temperature ≥37.3ºC were restricted from leaving First confirmed case reported in another province in China (in a person who had traveled from Wuhan); China CDC issued test reagent to all provinces in China
China CDC Level 2 emergency response activated Emergency monitoring, case investigation, close contact management, and market investigation initiated, technical protocols for Wuhan released; NHC notified WHO and relevant countries and regions; gene sequencing completed by China CDC
Outbreak Period
Linked to Huanan market Not linked to Huanan market
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Early Tr ansmission Dynamics of NCIP
interval [CI], 4.1 to 7.0); the 95th percentile of the distribution was 12.5 days (95% CI, 9.2 to 18) (Fig. 2A). We obtained information on 5 clusters of cases, shown in Figure 3. On the basis of the dates of illness onset of 6 pairs of cases in these clusters, we estimated that the serial interval distribution had a mean (±SD) of 7.5±3.4 days (95% CI, 5.3 to 19) (Fig. 2B). In the epidemic curve up to January 4, 2020, the epidemic growth rate was 0.10 per day (95% CI, 0.050 to 0.16) and the doubling time was 7. days (95% CI, 4.2 to 14). Using the serial interval distribution above, we estimated that R 0 was 2. (95% CI, 1.4 to 3.9). The duration from illness onset to first medical visit for 45 patients with illness onset before January 1 was estimated to have a mean of 5.8 days (95% CI, 4.3 to 7.5), which was similar to that for 207 patients with illness onset between January 1 and January 11, with a mean of 4.6 days (95% CI, 4.1 to 5.1) (Fig. 2C). The mean duration from onset to hospital admission was estimated to be 12.5 days (95% CI, 10.3 to 14.8) among 44 cases with illness onset before January 1, which was longer than that among 189 patients with illness onset between January
1 and 11 (mean, 9.1 days; 95% CI, 8.6 to 9.7) (Fig. 2D). We did not plot these distributions for patients with onset on or after January 12, be- cause those with recent onset and longer dura- tions to presentation would not yet have been detected.
Discussion
Here we provide an initial assessment of the transmission dynamics and epidemiologic char- acteristics of NCIP. Although the majority of the earliest cases were linked to the Huanan Sea- food Wholesale Market and the patients could have been infected through zoonotic or environ- mental exposures, it is now clear that human-to- human transmission has been occurring and that the epidemic has been gradually growing in recent weeks. Our findings provide important parameters for further analyses, including evalu- ations of the impact of control measures and predictions of the future spread of infection. We estimated an R 0 of approximately 2.2, meaning that on average each patient has been spreading infection to 2.2 other people. In gen- eral, an epidemic will increase as long as R 0 is
Characteristic
Before January 1 (N = 47)
January 1 –January 11 (N = 248)
January 12 –January 22 (N = 130) Median age (range) — yr 56 (26–82) 60 (21–89) 61 (15–89) Age group — no./total no. (%) <15 yr 0/47 0/248 0/ 15–44 yr 12/47 (26) 39/248 (16) 33/130 (25) 45–64 yr 24/47 (51) 106/248 (43) 49/130 (38) ≥65 yr 11/47 (23) 103/248 (42) 48/130 (37) Male sex — no./total no. (%) 31/47 (66) 147/248 (59) 62/130 (48) Exposure history — no./total no. (%) Wet market exposure 30/47 (64) 32/196 (16) 5/81 (6) Huanan Seafood Wholesale Market 26/47 (55) 19/196 (10) 5/81 (6) Other wet market but not Huanan Seafood Wholesale Market
4/47 (9) 13/196 (7) 0/
Contact with another person with respiratory symptoms
14/47 (30) 30/196 (15) 21/83 (25)
No exposure to either market or person with re- spiratory symptoms
12/27 (26) 141/196 (72) 59/81 (73)
Health care worker — no./total no. (%) 0/47 7/248 (3) 8/122 (7)
- Reduced denominators indicate missing data. Percentages may not total 100 because of rounding.
Table 1. Characteristics of Patients with Novel Coronavirus–Infected Pneumonia in Wuhan as of January 22, 2020.*
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Early Tr ansmission Dynamics of NCIP
would account for underrepresentation in the confirmed case count. Serosurveys after the first wave of the epidemic would clarify this question. Although infections in health care workers have been detected, the proportion has not been as high as during the SARS and MERS outbreaks.^15 One of the features of SARS and MERS out- breaks is heterogeneity in transmissibility, and in particular the occurrence of super-spreading events, particularly in hospitals.^16 Super-spread- ing events have not yet been identified for NCIP, but they could become a feature as the epidemic progresses. Although delays between the onset of illness and seeking medical attention were generally short, with 27% of patients seeking attention within 2 days after onset, delays to hospitaliza-
tion were much longer, with 89% of patients not being hospitalized until at least day 5 of illness (Fig. 2). This indicates the difficulty in identify- ing and isolating cases at an earlier stage of disease. It may be necessary to commit consider- able resources to testing in outpatient clinics and emergency departments for proactive case finding, both as part of the containment strategy in locations without local spread yet as well as to permit earlier clinical management of cases. Such an approach would also provide important infor- mation on the subclinical infections for a better assessment of severity. Our preliminary estimate of the incubation period distribution provides important evidence to support a 14-day medical observation period or quarantine for exposed persons. Our estimate
Figure 3. Detailed Information on Exposures and Dates of Illness Onset in Five Clusters Including 16 Cases. Numbers in boxes are calendar dates in December 2019 and January 2020. Data from the 5 secondary cases (patients who had clear exposure to only one index case and had no other potential source of infection) were used to estimate the serial interval distribution. The first four clusters were identified in Wuhan, and the fifth cluster was identified in Huanggang.
Case 2.1. F index 3
Onset Case 2.2. M
Cluster 2 (December 2019–January 2020) Onset 27
Case 3.1. M index 15
Onset Case 3.2. F
Case 3.3. M78 19
Onset
Case 3.4. M50 20
Onset
Cluster 3 (December 2019) Onset 12
22
Onset Case 4.2. M
Case 4.3. F25 24
Onset
Cluster 4 (December 2019) Case 4.1. F index
Onset 21
Case 1.1. M index
Case 1.3. F31 29
Onset
Cluster 1 (December 2019) Onset 20 Onset Case 1.2. F57 25
Exposure to wet market Exposure to other cases Exposure to wet market and other cases Exposure not determined
Case 5.1. M index 11
Onset Case 5.2. F
Case 5.3. M57 13
Onset
Case 5.4. F 16
Onset
Cluster 5 (January 2020) Onset 4
Case Serial Interval(days)
Data from the 5 Clusters Used in the Estimation of Serial Interval
5 9
3
7
7
7
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was based on information from 10 cases and is somewhat imprecise; it would be important for further studies to provide more information on this distribution. When more data become avail- able on epidemiologic characteristics of NCIP, a detailed comparison with the corresponding characteristics of SARS and MERS, as well as the four coronaviruses endemic in humans, would be informative. Our study suffers from the usual limitations of initial investigations of infections with an emerging novel pathogen, particularly during the earliest phase, when little is known about any aspect of the outbreak and there is a lack of diagnostic reagents. To increase the sensitivity for early detection and diagnosis, epidemiology history was considered in the case identification and has been continually modified once more information has become available. Confirmed cases could more easily be identified after the PCR diagnostic reagents were made available to Wuhan on January 11, which helped us shorten the time for case confirmation. Furthermore, the initial focus of case detection was on pa- tients with pneumonia, but we now understand that some patients can present with gastrointes- tinal symptoms, and an asymptomatic infection in a child has also been reported.^17 Early infec- tions with atypical presentations may have been missed, and it is likely that infections of mild clinical severity have been under-ascertained among the confirmed cases.^18 We did not have detailed information on disease severity for in- clusion in this analysis. In conclusion, we found that cases of NCIP have been doubling in size approximately every 7.4 days in Wuhan at this stage. Human-to-human transmission among close contacts has occurred since the middle of December and spread out gradually within a month after that. Urgent next
steps include identifying the most effective con- trol measures to reduce transmission in the community. The working case definitions may need to be refined as more is learned about the epidemiologic characteristics and outbreak dy- namics. The characteristics of cases should continue to be monitored to identify any chang- es in epidemiology — for example, increases in infections among persons in younger age groups or health care workers. Future studies could in- clude forecasts of the epidemic dynamics and special studies of person-to-person transmission in households or other locations, and serosur- veys to determine the incidence of the subclini- cal infections would be valuable.^14 These initial inferences have been made on a “line list” that includes detailed individual information on each confirmed case, but there may soon be too many cases to sustain this approach to surveillance, and other approaches may be required.^19 The views expressed in this article are those of the authors and do not represent the official policy of the China CDC. All the authors have declared no relationships or activities that could appear to have influenced this work. Supported by the Ministry of Science and Technology of Chi- na, the National Science and Technology Major Projects of China (2018ZX10201-002-008-002, 2018ZX10101002-003), the China– U.S. Collaborative Program on Emerging and Re-emerging In- fectious Disease, and National Mega-Projects for Infectious Disease (2018ZX10201002-008-002), the National Natural Sci- ence Foundation (71934002), the National Institute of Allergy and Infectious Diseases (Centers of Excellence for Influenza Research and Surveillance [CEIRS] contract number HH- SN272201400006C), and the Health and Medical Research Fund (Hong Kong). None of the funders had any role in the study de- sign and the collection, analysis, and interpretation of data or in the writing of the article and the decision to submit it for publi- cation. The researchers confirm their independence from funders and sponsors. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Wuhan CDC, Huanggang CDC, and other prefec- ture CDCs and medical institutions in Wuhan for assistance with field investigation administration and data collection and the National Institute for Viral Disease Control and Prevention, China CDC, for assistance with laboratory testing.
Appendix The authors’ affiliations are as follows: the Chinese Center for Disease Control and Prevention, Beijing (Q.L., X.W., L.Z., R.R., N.X., C.L., D.L., J.Z., W.T., L.J., Q.W., R.W., Y.Z., G. Shi, G.F.G., Z.F.), the Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei (X.G., Y.T., X.X., Y.W., Q.C., M.L., C.C., R.Y., S.Z., Y. Luo, B.Y.), the World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, University of Hong Kong, Hong Kong (P.W., K.S.M.L., E.H.Y.L., J.Y.W., T.T.Y.L., J.T.W., B.J.C., G.M.L.), the Chinese Field Epidemiology Training Program, Chinese Center for Disease Con- trol and Prevention, Beijing (T.L., R.Y., S.Z., H. Liu, Y. Liu, G. Shao, H. Li, Z.T.), the Jingzhou Center for Disease Control and Preven- tion, Jingzhou, Hubei (T.L.), the Chengdu Center for Disease Control and Prevention, Chengdu, Sichuan (H. Liu); the Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan (Y. Liu), the Anyang Municipal Center for Disease Control and Prevention, Anyang, Henan (G. Shao), the Panjin Center for Disease Control and Prevention, Panjin, Liaoning (H. Li), the Guizhou Center for Dis- ease Control and Prevention, Guiyang, Guizhou (Z.T.), the Jiading District Center for Disease Control and Prevention, Shanghai (Y.Y.), the Nanchang Center for Disease Control and Prevention, Nanchang, Jiangxi (Z.D.), the Inner Mongolia Comprehensive Center for Disease Control and Prevention, Hohhot, Inner Mongolia (B.L.), and the Baoshan District Center for Disease Control and Prevention, Shanghai (Z.M.) — all in China.
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