《内科学》课程教学资源（新冠文献）Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

The NEW ENGLAND JOURNAL f MEDICINE ORIGINAL ARTICLE Early Transmission Dynamics in Wuhan,China, of Novel Coronavirus-Infected Pneumonia Kathy S.M.Leung.Ph.D..Eric H.Y.Lau,Ph.D.Jessica Y.Wong.Ph.D. Xuesen Ph.Njuan M.Med.Yang Wu Mc.P.H. Man i en. Rui Yang.M.Med.Oi Wang.M.P.H.Suhua Zhou.M.Med.Rui Wane.M.D. Hui Liu,M.Med.,Yinbo Luo,M.Sc..Yuan Liu,M.Med.,Ge Shao,B.Med., Huan Li,M.P.H.Zhongfa Tao,M.P.H.,YangYang,M.Med. M.Me L n Bo Yang,M.Sc..Gabriel M.Leung,M.D.and Zijian Feng,M.Med. ABSTRACT BACKGROUND The initial c eof novel coronus 1Cov)infted pneumoni (N) er2019 and eng at the d Pr ing District.Bi ing.C on on de ic characteri sure history, Gogt d by of January 22,2020.We described characteristics of the cases and estimated the kev time-deyinthe priod ofonhwe at the Hubei Ce y:or to D estimated the epidemic doubling time and the basic reproductive number. Control a Prevention,Ne the first 425 atithid NCIP thedia Hubei.China.or. and 56 er The majority of cases (55%)with onset before an were linked to the Huanan Seafo Wholesale Market,as compared with 959 artide tages the epidemic doubled in size every 4 ays.With a mean serial interal of 7.5 days%Cl,5.3 to1),the basic reproductive number was estimated to be 20 2.295%C1.1.4to3.9). eais of this normtion there is evidence that 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 amics apply el nistry o N ENGLI MED NEIMORO

The new england journal o f medicine n engl j med nejm.org 1 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 31, 2020, at NEJM.org. DOI: 10.1056/NEJMoa2001316 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.) ABSTRACT 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., Yinbo 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 The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL Of MEDICINE INCE DECEMBER 2019.AN INCREASING Data were collected onto standardized form number of cases of novel coronavirus through interviews of infected persons,rela (2019-nCoV)-infected pneumonia (NCIP tives,close and health care wor have been identified in Wuhan,a large city of 11 ts to clinical fac an es.Ep ata wer Market were identified hy local hospitals using surveillance mechanism for"pneumonia of un fection and their relatives where necessary to known etiology"that was established in the wake determine exposure histories during the 2 weeks of the 2003 severe acute respiratory syndrom before the illness onset,including the dates,time (SARS outbre k with the aim of allowing timel ncy,and patter to any wil d tion c suc H.espec se cities and in e than es to dozen countries around the worlds Her ments such as that specific market or other we provide an analysis of data on the first 425 lab markets.Information about contact with other oratory-confirmed cases in Wuhan to describe the with similar symptoms was also included.A epidemiologic characteristics and transmission epidemiologic info ation collecte during fiel NCI ng exposure METHODS ces.Households a and nlace SOURCES OF DATA have heen visited by the patients in the 2 weel The earliest cases were identified through the before the onset of illness were also investigated 'pneumonia of unknown etiology"surveillance to assess for possible animal and environmenta mechanism.P own etiology i exposures ata were ve pa in dup d were ver ed with Epi 38C)radio Da nia low or normal white-cell count or low lym CASE DEFINITIONS ohocyte count,and no symptomatic improven The initial working case definitions for suspected after antimicrobial treatment for 3 to 5 days fol- NCIP were based on the SARS and Middle East lowing standard clinical guidelines.In respons to th rea by th de 2012 de on 32020 fulfilled all th sing the case definitions des with or without remperature:radio a suspected case was identified,the joint field graphic evidence of pneumonia;low or normal epidemiology team comprising members from white-cell count or low lymphocyte count;and the Chine Center for Disease Co ntrol and Pre trea nt for 3 ay ed field in ions and collect resniratory specimens for to the Huanan Seafood Wholesale Marke t or cor tralized testing at the national institute for viral tact with other patients with similar symntom Disease Control and Prevention.China CDC.in The epidemiologic criteria to define a suspectec case were update d on January 18.2020.once CDO sconducted detailed fie information on ide ses becam for all suspected and confirmec ng:a t N ENGLJ MED NEJM.ORG The New En and Journal of Medicin oaded from nejm.M All right

2 n engl j med nejm.org The new england journal o f medicine 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. Methods 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 The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

EARLY TRANSMISSION DYNAMICS OF NCIP distrns were case was defined as a case with resniratory medical visit and ho spital admission in a subse mens that tested positive for the 2019-nCov by at of cases with detailed information available.We least one of the following three methods:isola-fitted a gamma distribution to data from cluster tion of 2019-nCov or at least two positive results inve stigations to estimate the serial interval dis by real-tim reverse-transcriptio -polymera tribut n,defined as the delay betv een ilnes cham-e CR)assay or Cov or onset dates in successive cases in chains of tran genet We estimated the owth rate by LABORATORY TESTING ases with illness onse The 2019-nCoV laboratory test ass ys were based between December 10 and January 4,because we on the previous WHO recommendation.Uppe expected the proportion of infections identified er respiratory tra specimens were ob would in crease soon after the formal announce ron ract an outbrea er real-tin with in Wuhan on De 2019-n e fitte in b pri set dates that w ot linked to the Huanan seafood wholesale market and we for viral Disease Control at China CDC.If two used this model to derive the epidemic growth targets (open reading frame la or 1b,nucleocap rate,the epidemic doubling time,and the basic e by spec ic real-tim number (R),whi n is defined as cas the ex cted numbe r of s that on (less than 3 was defin a its infe test,and a Ct-value of 40 or mo vas defined a ulation We used an info ior dist a negative test.A medium load,defined as a Ctvalue bution for the serial interval based on the serial of 37 to less than 40,required confirmation by interval of SARS with a mean of 8.4 and a stan- d Ct-value was less dard c ation of 3.8.' an obvious pea s than 37th d,or if Analyse tion period,s an . Th of bro the patient by one of three methods:Sange se. quencing,Illumina sequencing,or nanopore se- dation for Statistical Computing). quencing.Respiratory specimens were inocula e C d biosafety ETHICS ata collectio and ana sis of es and conacts were c fthe pec The epidemic curve was constructed by date of be part of a continuing public health outbreak illness onset and key dates relatine to epidemi investigation and were thus considered exempt identification and control measures were overlaid from institutional review board approval to aid int erpretation. Case characteristics were described,inc g c mographic chara RESULTS me The deve tion to illnes lopmen of the epidemic follow tia h in nd a de fitting a log-normal distribution to data on e most recent days is likely to he due to under posure histories and onset dates in a subset of ascertainment of cases with recent onset and cases with c tailed information available.Onse delayed identification and r orting rather than to-first-medical-visit and onset-to-admission dis a true turning point in incidence(Fig 1).Spe N ENGLIMED NEIM.OR Downloaded from nejm.og at SOUTHERN MEDICAL UNIVERSITY h6,2020.F opyngnt 2020 N

n engl j med nejm.org 3 Early Transmission Dynamics of NCIP Wuhan who had fever or respiratory symptoms, within 14 days before illness onset.9 A confirmed case was defined as a case with respiratory speci￾mens that tested positive for the 2019-nCoV by at least one of the following three methods: isola￾tion of 2019-nCoV or at least two positive results by real-time reverse-transcription–polymerase￾chain-reaction (RT-PCR) assay for 2019-nCoV or a genetic sequence that matches 2019-nCoV. Laboratory Testing The 2019-nCoV laboratory test assays were based on the previous WHO recommendation.10 Upper and lower respiratory tract specimens were ob￾tained from patients. RNA was extracted and tested by real-time RT-PCR with 2019-nCoV–spe￾cific primers and probes. Tests were carried out in biosafety level 2 facilities at the Hubei (pro￾vincial) CDC and then at the National Institute for Viral Disease Control at China CDC. If two targets (open reading frame 1a or 1b, nucleocap￾sid protein) tested positive by specific real-time RT-PCR, the case would be considered to be laboratory-confirmed. A cycle threshold value (Ct-value) less than 37 was defined as a positive test, and a Ct-value of 40 or more was defined as a negative test. A medium load, defined as a Ct-value of 37 to less than 40, required confirmation by retesting. If the repeated Ct-value was less than 40 and an obvious peak was observed, or if the repeated Ct-value was less than 37, the retest was deemed positive. The genome was identified in samples of bronchoalveolar-lavage fluid from the patient by one of three methods: Sanger se￾quencing, Illumina sequencing, or nanopore se￾quencing. Respiratory specimens were inoculat￾ed in cells for viral isolation in enhanced biosafety laboratory 3 facilities at the China CDC.3 Statistical Analysis The epidemic curve was constructed by date of illness onset, and key dates relating to epidemic identification and control measures were overlaid to aid interpretation. Case characteristics were described, including demographic characteristics, exposures, and health care worker status. The incubation period distribution (i.e., the time delay from infection to illness onset) was estimated by fitting a log-normal distribution to data on ex￾posure histories and onset dates in a subset of cases with detailed information available. Onset￾to-first-medical-visit and onset-to-admission dis￾tributions were estimated by fitting a Weibull distribution on the dates of illness onset, first medical visit, and hospital admission in a subset of cases with detailed information available. We fitted a gamma distribution to data from cluster investigations to estimate the serial interval dis￾tribution, defined as the delay between illness onset dates in successive cases in chains of trans￾mission. We estimated the epidemic growth rate by analyzing data on the cases with illness onset between December 10 and January 4, because we expected the proportion of infections identified would increase soon after the formal announce￾ment of the outbreak in Wuhan on December 31. We fitted a transmission model (formulated with the use of renewal equations) with zoonotic in￾fections to onset dates that were not linked to the Huanan Seafood Wholesale Market, and we used this model to derive the epidemic growth rate, the epidemic doubling time, and the basic reproductive number (R0 ), which is defined as the expected number of additional cases that one case will generate, on average, over the course of its infectious period in an otherwise uninfected population. We used an informative prior distri￾bution for the serial interval based on the serial interval of SARS with a mean of 8.4 and a stan￾dard deviation of 3.8.11 Analyses of the incubation period, serial in￾terval, growth rate, and R0 were performed with the use of MATLAB software (MathWorks). Other analyses were performed with the use of SAS software (SAS Institute) and R software (R Foun￾dation for Statistical Computing). Ethics Approval Data collection and analysis of cases and close contacts were determined by the National Health Commission of the People’s Republic of China to be part of a continuing public health outbreak investigation and were thus considered exempt from institutional review board approval. Results The development of the epidemic follows an ex￾ponential growth in cases, and a decline in the most recent days is likely to be due to under￾ascertainment of cases with recent onset and delayed identification and reporting rather than a true turning point in incidence (Fig. 1). Spe￾The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL Of MEDICINE Linked to Huanan market Not linked to Huanan market A novel coro CR diagnostic reagents provided to Wuhan by China CDC 45 WHC Huaeo irst con eported in anothe R8crS provinces 10- 5811141720 Nov. Dec n 2019 Outbreak Period 2020 The declir after sis and lat ssion and wHo World Health orea cifically,the latter part of the curve doe first period was for ain nt a Seafood wholesale Marke the cutoff date.Care should be taken in inter- second period was for those with onset betweer preting the speed of growth in cases in January,January 1 and January 11,which was the date given an increase in the availability and use of when RT-PCR reagents were provided to Wuhan testing kits as time has progressed.The major- and the third period was tho e with illness onse ity c est cases m 0 or al r January 12 (Tab 1).The patient bure to he in e were number of nonlinked cases beginning in late ure to the Huanan Seafood December Market The pro portion of cases in health care The median age of the patients was 59 years workers gradually increased across the three (range,15 to 89),and 240 of the 425 patients periods (Table 1). (56%)were male .Ther e were no case in chil We examined data on exposures w ye we the days(9%conf N ENGLJ MED NEJM.ORC The New Eng Downloaded from ejm.ga SOUTHERN ME land Joural of Medicine s Mo

4 n engl j med nejm.org The new england journal o f medicine 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 The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

EARLY TRANSMISSION DYNAMICS OF NCIP Table .Characteristics of Patients with Novel Co onavirus-nfected Pneumonia in Wuhanas of. Characteristi Median age(range)一yt 56(26-82 60(21-39 61(15-89) Age group-no./total no.(9) c15vt 0/47 0248 0130 15-44yT 27间 39/248(16 33130(25) 45-64y 24/47(51 106/24843 49/130(38) ≥65y7 11/47(23) 103/248(42 48/130(37 Male sex- -no./total no.(9) 31/47(66 147/248(59 62/130(48 Exposure history-no./total no.(% Wet market exposure 30/4764) 32/19616 581(6 Huanan seafood wholesale marke 26/47(55 19/19610 5/81(同间 Othe 3/196( 14/47(30) 30/196(15) 21/83(25 12147(2 141/n96(72 5981(73到 Health care worker-no./total no.(% 0/47 7/248(3) 8/122(0 Reduced denominators indicate missing data.Percentages may not total 100 because of rounding. interval [CI],4.1 to 7.0);the 95th percentile of 1 and 11 (mean,9.1 days;95%CI,8.6 to 9.7) the distribution was 12.5 days(%CL,9.2 to 18)(Fig.2D).We did not plot these distributions for (Fig.2A).We obtained information on 5 clusters patients with onset on or after January 12,be- onse in thes that distribution had a mean SD)of 53.4 days 95%CL,5.3to19Fig2B). In the epidemic curve up to January 4,2020 DISCUSSION the epidemic growth rate was 0.10 per day(%Here we provide an initial assessment of the CI,0.050 to 0.16)and the doubling time was 7.4 2t014.0s ing the h ugh jority or th and th The duration from illness onset to first have been infected through zoonotic or environ- medical visit for 45 patients with illness onset mental exposures,it is now clear that human-to- before January 1 was estimated to have a mean human transmission has been occurring and of 5.8 days (9%Cl,4.3 to 7.5),which was that the epidemic has been graduall ly growing in similar to that fo patients w ss onset recent wee Our findings provid rther a includ mg eva ys diction of to h cod of infe was estimated to be 12.5 days (9%CI.10.3 to We estimated an R of approximately 2.2. 14.8)among 44 cases with illness onset before meaning that on average each patient has been January 1,which w spreading infection to 2.2 other people.In gen- N ENGLIMED NEIM.ORO 5 nal us

n engl j med nejm.org 5 Early Transmission 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 7.4 days (95% CI, 4.2 to 14). Using the serial interval distribution above, we estimated that R0 was 2.2 (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 R0 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 R0 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 0/130 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) 0/81 Contact with another person with respiratory symptoms 14/47 (30) 30/196 (15) 21/83 (25) No exposure to either market or person with respiratory symptoms 12/47 (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.* The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL Of MEDICINE 025 020 015 .10 0.05 0.05 0.0 ys from Infection to s n Onse Serial er(days) D 025 二8 u1n 020 0.10 0.10 .0 .0 Days fro Onset to First M Days from lliness Onset to Hospitalizati Figure 2.Key Time-to-Event Distributions. The estimated incubation d distribution(e.the time from infection toness onset)is shown in Panel A.Th own in Panel B. The est aeddetrbUtio s of time The estimated distributions of times from illness onset toh greater than 1, and contro to less e wo ued to ntin of Wuh citie isolation of patients and careful infection con since lanuary 23 should reduce the exportation trol.In the case of NCIP,challenges to control of cases to the rest of the country and overseas include the apparent presence of many mild in- it is now a priority to determine whether loca fections and limited d resources for isolation of transmi ssion at a similar intensity is occurring cases and qua their clo se con in other lod R was limitec the period that few of the outbreak and greater availability and use of tests were in adults 60 years of age or older,altho in more recent weeks will have increased the our case definition specified severe enough ill proportions of infections ascertained.It is pos ness to require medical attention,which may vary sible that subsequent control measures in Wu according to the pres nce of coexisting cond han, tions.Furthermore, child night be less lik e ransm come inrectec nte of the may shov N ENGLJ MED NEJM.ORG The New Eng land Joural of Medicine Downloaded from nejm.ogat SOUTHERN ME

6 n engl j med nejm.org The new england journal o f medicine greater than 1, and control measures aim to re￾duce the reproductive number to less than 1. The R0 of SARS was estimated to be around 3,12 and SARS outbreaks were successfully controlled by isolation of patients and careful infection con￾trol.13 In the case of NCIP, challenges to control include the apparent presence of many mild in￾fections14 and limited resources for isolation of cases and quarantine of their close contacts. Our estimate of R0 was limited to the period up to January 4 because increases in awareness of the outbreak and greater availability and use of tests in more recent weeks will have increased the proportions of infections ascertained. It is pos￾sible that subsequent control measures in Wu￾han, and more recently elsewhere in the country as well as overseas, have reduced transmissibil￾ity, but the detection of an increasing number of cases in other domestic locations and around the world suggest that the epidemic has contin￾ued to increase in size. Although the population quarantine of Wuhan and neighboring cities since January 23 should reduce the exportation of cases to the rest of the country and overseas, it is now a priority to determine whether local transmission at a similar intensity is occurring in other locations. It is notable that few of the early cases oc￾curred in children, and almost half the 425 cases were in adults 60 years of age or older, although our case definition specified severe enough ill￾ness to require medical attention, which may vary according to the presence of coexisting condi￾tions. Furthermore, children might be less likely to become infected or, if infected, may show milder symptoms, and either of these situations Figure 2. Key Time-to-Event Distributions. The estimated incubation period distribution (i.e., the time from infection to illness onset) is shown in Panel A. The estimated serial interval distribution (i.e., the time from illness onset in successive cases in a transmission chain) is shown in Panel B. The estimated distributions of times from illness onset to first medical visit are shown in Panel C. The estimated distributions of times from illness onset to hospital admission are shown in Panel D. A 0 7 14 21 0.00 0.05 0.10 0.25 0.20 0.15 Days from Infection to Symptom Onset B 0 7 14 21 0.00 0.05 0.10 0.20 0.15 Serial Interval (days) 0 3 6 9 12 0.00 0.05 0.10 0.15 0.20 0.25 Days from Illness Onset to First Medical Visit Onset before January 1 Onset during January 1−11 C 0 10 20 30 0.00 0.05 0.10 0.15 Days from Illness Onset to Hospitalization Relative Frequency Relative Frequency Relative Frequency Relative Frequency D Onset before January 1 Onset during January 1−11 The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

EARLY TRANSMISSION DYNAMICS OF NCIP Cluster 1 (December 2019) Cluster 5 ganuary 2020) eaw卫 cw中 case12F575 cas0s2.2s回 case13F319 ce53.Ms,工 Cluster2 (December 2019-January 2020) ases4.6☐ ce21卫 Case22.M64 aomhs Cluster3(December 201) ce1,8工 cae2r国工 13 ae3.M8四D 43 caeAwso0D cae卫 cae42wsID nd other cases case43.2s4□ Figure 3.Detailed Exposures and Dates ofness Onset in Five Clusters Including 16Cases. he first four usters were identified in Wuhan,and the fifth custer was would account for underrepresentation in the tion were much longer,with 89%of patients not wave of epidemic wot dicates the difficult y in identif alt larify this question ad the on has not he It ma cases an ea high as during the SARS and MERS outbreaks.able resources to testing in outpatient clinics One of the features of SARS and MERS out-and emergency departments for proactive case breaks is heterogeneity in transmissibility,and finding,both as part of the containment strategy in particular the rence of super-spreading in locations wi hout local spread yet as well as to permit earlier clinical manage de super-spreac ent of cases. an appro. ecomea feature as the epidemic delays betwen the of Our preliminary estimate of the incubation and seeking medical attention were generally period distribution provides important evidence short,with 27%of patients seeking attention to support a 14-day medical observation period within 2 days after onset,delays to hospitaliza-or quarantine for exposed persons.Our estimate N ENGLIMED NEIM.ORO nal us Copyngnt 2020 Mas

n engl j med nejm.org 7 Early Transmission 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. F62 index 3 Onset Case 2.2. M64 Cluster 2 (December 2019–January 2020) Onset 27 Case 3.1. M49 index 15 Onset Case 3.2. F48 Case 3.3. M78 19 Onset Case 3.4. M50 20 Onset Cluster 3 (December 2019) Onset 12 22 Onset Case 4.2. M51 Case 4.3. F25 24 Onset Cluster 4 (December 2019) Case 4.1. F52 index Onset 21 Case 1.1. M61 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. M32 index 11 Onset Case 5.2. F28 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 1.2 1.3 2.2 3.3 4.3 5.2 The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL Of MEDICINE was based on information from 10 cases and is steps include identifving the most effective con somewhat imprecise:it would be important for trol measures to reduce transmission in the urther studies to provide more information on community.The working case definitions may this distribution.When more data become avail- need to be refined as more is learned about the racteristics of NCI， cases four co endemic in humans would es in epidemiology-for example increases be informative. infections among persons in younger age group Our study suffers from the usual limitations or health care workers.Future studies could in of initial investigations of infections with an clude forecasts of the epidemic dynamics and the special stud es of person-to-person transmissior own d th or otne tons,and s eagents.To incr ase the for early detection and diag osis inferences have heen made on a "line list"tha history was considered in the case identification includes detailed individual information on each and has been continually modified once more confirmed case,but there may soon be too many ailable cases to sustain nore easily be lable t The views expe the time for case confirm the initial focus of case detection was on pa d this y ence tients with pneumonia,but we now understand the Natic S and Te that some patients can present with gastrointes- rging and R ing In for In in a chi nas rly infec adation (71934002)the Na inf may clinical severity have been under-ascertaine among the confirmed cases.We did not have detailed information on disease severity for in- ndnpoanof clusion in this analysis. nd that cases of NCII s oximately ever Wu stag nta ha since the middle of December and spread ou gradually within a month after that.Urgent next and Pr the Wor .J.Y.W..T.T .the Chengd a.Hu n (Y.Liu) T.).th iading Di ZD) he er M n District N ENGLJ MED NEJM.ORG The New England Journal of Medicin Downloaded from nejm.ong at SOUTHERN ME

8 n engl j med nejm.org The new england journal o f medicine 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. The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved

EARLY TRANSMISSION DYNAMICS OF NCIP V).SARS a irus g d2014370:2 505 Wuhan.Chin Gao GF.MERS.SARS. Zhu N.Zhang D,Wang W,et al. progra 202 Cell Host Microbe1: who.int/ A(H7N9) D%011917490 013.Emerg Infect h M.Cohe and co China, 20 P. FG,Cowling B 16e791-801 for 374:12 9-1 res N ENGLI MED NEIM.ORO 9 nal of medici Downloaded MEDICAL.Fo onalusconly.NootherusesWithoutpemlsioa

n engl j med nejm.org 9 Early Transmission Dynamics of NCIP References 1. The 2019-nCoV Outbreak Joint Field Epidemiology Investigation Team, Li Q. Notes from the field: an outbreak of NCIP (2019-nCoV) infection in China — Wu￾han, Hubei Province, 2019–2020. China CDC Weekly 2020;2:79-80. 2. Tan WJ, Zhao X, Ma XJ, et al. A novel coronavirus genome identified in a clus￾ter of pneumonia cases — Wuhan, China 2019–2020. China CDC Weekly 2020;2:61-2. 3. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. DOI: 10.1056/NEJMoa2001017. 4. Xiang N, Havers F, Chen T, et al. Use of national pneumonia surveillance to de￾scribe influenza A(H7N9) virus epidemi￾ology, China, 2004–2013. Emerg Infect Dis 2013;19:1784-90. 5. Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A novel coronavirus emerging in China — key questions for impact assessment. N Engl J Med. DOI: 10.1056/NEJMp2000929. 6. WHO guidelines for the global sur￾veillance of severe acute respiratory syn￾drome (SARS). 2004 (https://www.who .int/csr/resources/publications/WHO _CDS_CSR_ARO_2004_1.pdf?ua=1). 7. Middle East respiratory syndrome case definition for reporting to WHO. 2017 (https://www.who.int/csr/disease/ coronavirus_infections/mers-interim-case -definition.pdf?ua=1). 8. Azhar EI, El-Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human trans￾mission of MERS coronavirus. N Engl J Med 2014;370:2499-505. 9. New coronavirus pneumonia prevention and control program (2nd ed.) (in Chinese). 2020 (http://www.nhc.gov.cn/jkj/s3577/ 202001/c67cfe29ecf1470e8c7fc47d3b751e88 .shtml). 10. Laboratory diagnostics for novel coro￾navirus. WHO 2020 (https://www.who.int/ health-topics/coronavirus/laboratory -diagnostics-for-novel-coronavirus). 11. Lipsitch M, Cohen T, Cooper B, et al. Transmission dynamics and control of severe acute respiratory syndrome. Sci￾ence 2003;300:1966-70. 12. Bauch CT, Lloyd-Smith JO, Coffee MP, Galvani AP. Dynamically modeling SARS and other newly emerging respiratory ill￾nesses: past, present, and future. Epide￾miology 2005;16:791-801. 13. Paules CI, Marston HD, Fauci AS. Coronavirus infections — more than just the common cold. JAMA 2020 January 23 (Epub ahead of print). 14. Perlman S. Another decade, another coronavirus. N Engl J Med. DOI: 10.1056/ NEJMe2001126. 15. de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016;14:523-34. 16. Wong G, Liu W, Liu Y, Zhou B, Bi Y, Gao GF. MERS, SARS, and Ebola: the role of super-spreaders in infectious disease. Cell Host Microbe 2015;18:398-401. 17. Chan JF, Yuan S, Kok KH, et al. A fa￾milial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020 January 24 (Epub ahead of print). 18. Wu P, Hao X, Lau EHY, et al. Real￾time tentative assessment of the epide￾miological characteristics of novel coro￾navirus infections in Wuhan, China, as at January 2020. Eurosurveillance 2020; 25(3):pii=2000044. 19. Lipsitch M, Hayden FG, Cowling BJ, Leung GM. How to maintain surveillance for novel influenza A H1N1 when there are too many cases to count. Lancet 2009; 374:1209-11. Copyright © 2020 Massachusetts Medical Society. The New England Journal of Medicine Downloaded from nejm.org at SOUTHERN MEDICAL UNIVERSITY on March 6, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved