Stephen A. Lauer, MS, PhD *; Kyra H. Grantz, BA *; Qifang Bi, MHS; Forrest K. Jones, MPH; Qulu Zheng, MHS; Hannah R. Meredith, PhD; Andrew S. Azman, PhD; Nicholas G. Reich, PhD; Justin Lessler, PhD
Acknowledgment: The authors thank all who have collected, prepared, and shared data throughout this outbreak. They are particularly grateful to Dr. Kaiyuan Sun, Ms. Jenny Chen, and Dr. Cecile Viboud from the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health; Dr. Moritz Kraemer and the open COVID-19 data working group; and the Johns Hopkins Center for Systems Science and Engineering.
Grant Support: By the U.S. Centers for Disease Control and Prevention (NU2GGH002000), the National Institute of Allergy and Infectious Diseases (R01 AI135115), the National Institute of General Medical Sciences (R35 GM119582), and the Alexander von Humboldt Foundation.
Disclosures: Dr. Lauer reports grants from the National Institute of Allergy and Infectious Diseases and the U.S. Centers for Disease Control and Prevention during the conduct of the study. Ms. Grantz reports a grant from the U.S. Centers for Disease Control and Prevention during the conduct of the study. Dr. Reich reports grants from the National Institute of General Medical Sciences and the Alexander von Humboldt Foundation during the conduct of the study. Dr. Lessler reports a grant from the U.S. Centers for Disease Control and Prevention during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-0504.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: Not applicable. Statistical code and data set: Available at https://github.com/HopkinsIDD/ncov_incubation.
Corresponding Author: Justin Lessler, PhD, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205; e-mail, email@example.com.
Current Author Addresses: Drs. Lauer, Meredith, and Lessler; Ms. Grantz; Ms. Bi; Mr. Jones; and Ms. Zheng: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205.
Dr. Azman: Médecins Sans Frontières, Rue de Lausanne 72, 1202 Genève, Switzerland.
Dr. Reich: Department of Biostatistics and Epidemiology, Amherst School of Public Health and Health Sciences, University of Massachusetts, 715 North Pleasant Street, Amherst, MA 01003-9304.
Author Contributions: Conception and design: S.A. Lauer, K.H. Grantz, F.K. Jones, N.G. Reich, J. Lessler.
Analysis and interpretation of the data: S.A. Lauer, K.H. Grantz, Q. Bi, F.K. Jones, N.G. Reich, J. Lessler.
Drafting of the article: S.A. Lauer, K.H. Grantz, Q. Bi, F.K. Jones, A.S. Azman, N.G. Reich.
Critical revision of the article for important intellectual content: Q. Bi, F.K. Jones, A.S. Azman, N.G. Reich, J. Lessler.
Final approval of the article: S.A. Lauer, K.H. Grantz, Q. Bi, F.K. Jones, Q. Zheng, H.R. Meredith, A.S. Azman, N.G. Reich, J. Lessler.
Statistical expertise: Q. Bi, N.G. Reich, J. Lessler.
Collection and assembly of data: S.A. Lauer, K.H. Grantz, Q. Bi, F.K. Jones, Q. Zheng, H.R. Meredith.
Previous Posting: This manuscript was posted as a preprint on medRxiv on 4 February 2020. doi:10.1101/2020.02.02.20020016
A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in China in December 2019. There is limited support for many of its key epidemiologic features, including the incubation period for clinical disease (coronavirus disease 2019 [COVID-19]), which has important implications for surveillance and control activities.
To estimate the length of the incubation period of COVID-19 and describe its public health implications.
Pooled analysis of confirmed COVID-19 cases reported between 4 January 2020 and 24 February 2020.
News reports and press releases from 50 provinces, regions, and countries outside Wuhan, Hubei province, China.
Persons with confirmed SARS-CoV-2 infection outside Hubei province, China.
Patient demographic characteristics and dates and times of possible exposure, symptom onset, fever onset, and hospitalization.
There were 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. The median incubation period was estimated to be 5.1 days (95% CI, 4.5 to 5.8 days), and 97.5% of those who develop symptoms will do so within 11.5 days (CI, 8.2 to 15.6 days) of infection. These estimates imply that, under conservative assumptions, 101 out of every 10 000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine.
Publicly reported cases may overrepresent severe cases, the incubation period for which may differ from that of mild cases.
This work provides additional evidence for a median incubation period for COVID-19 of approximately 5 days, similar to SARS. Our results support current proposals for the length of quarantine or active monitoring of persons potentially exposed to SARS-CoV-2, although longer monitoring periods might be justified in extreme cases.
U.S. Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, and Alexander von Humboldt Foundation.
SARS-CoV-2 exposure (blue), symptom onset (red), and case detection (green) times for 181 confirmed cases.
Shaded regions represent the full possible time intervals for exposure, symptom onset, and case detection; points represent the midpoints of these intervals. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Table 1. Characteristics of Patients With Confirmed COVID-19 Included in This Analysis (n = 181)*
Cumulative distribution function of the COVID-19 incubation period estimate from the log-normal model.
The estimated median incubation period of COVID-19 was 5.1 days (CI, 4.5 to 5.8 days). We estimated that fewer than 2.5% of infected persons will display symptoms within 2.2 days (CI, 1.8 to 2.9 days) of exposure, whereas symptom onset will occur within 11.5 days (CI, 8.2 to 15.6 days) for 97.5% of infected persons. Horizontal bars represent the 95% CIs of the 2.5th, 50th, and 97.5th percentiles of the incubation period distribution. The estimate of the dispersion parameter is 1.52 (CI, 1.32 to 1.72). COVID-19 = coronavirus disease 2019.
Appendix Table 1. Percentiles of SARS-CoV-2 Incubation Period From Selected Sensitivity Analyses*
Appendix Table 2. Parameter Estimates for Various Parametric Distributions of the Incubation Period of SARS-CoV-2 Using 181 Confirmed Cases*
Proportion of known symptomatic SARS-CoV-2 infections that have yet to develop symptoms, by number of days since infection, using bootstrapped estimates from a log-normal accelerated failure time model.
Table 2. Expected Number of Symptomatic SARS-CoV-2 Infections That Would Be Undetected During Active Monitoring, Given Varying Monitoring Durations and Risks for Symptomatic Infection After Exposure*
Richard M Fleming, PhD, MD, JD; Matthew R Fleming, BS, NRP; Tapan K Chaudhuri, MD
FHHI-OI-Camelot; FHHI-OI-Camelot; Eastern Virginia Medical School
March 10, 2020
Conflict of Interest:
No COI to declare.
The greatest thing we have to fear from CoVid-19.
This coronavirus is behaving exactly like a virus. By that we mean it is transmitted in specific ways: it attaches to certain tissues within the body and its goal is not to kill its host but to survive within the host.If we knew nothing more, that should be enough to calm our fears and promote cooperation among all of us: that should be enough to halt the run on store products and stop the price gouging of tissue, hand cleaner and other items; and while calmly promoting restoration of the stock market, the world economy, and our countries. Why? Because this is not some unknown enemy attacking us that we don’t know how to deal with. This virus is transmitted by people sneezing or coughing on you. Masks are for those people who are coughing and sneezing—for them to wear to reduce their coughing or sneezing their virus upon you—not for you to wear when you’re not the one coughing or sneezing. This behavior of everyone wearing masks doesn’t stop the spread; in fact it may increase the potential for warm moist areas for the virus to survive and it promotes unnecessary fear. (1) A major method of spreading the virus includes touching your face with your hands and then spreading the virus by touching others, as well as increasing the likelihood of further infecting yourself with more of the virus. As Ignaz Semmelweis demonstrated more than 150 years ago, hand washing (hand soap) dramatically reduces the transmission of pathogens from person to person.(2) The virus attaches itself to the lungs and GI track, where IgA is primarily responsible for addressing immunologic responses. This means we know what to look for and what to treat, allowing those who are sickest to be best-taken care of. This is why we see the elderly immune-compromised and those with heart and lung problems most susceptible.(3) Viruses don’t try to kill their host. If they were successful at that, it would prevent them from reproducing themselves and surviving.CoVid-19 also presents us with the opportunity to learn and potentially develop new treatments for IgA disorders, CAD, and cancer. This is not some unknown invader which we need to fear. This is a virus with all the limitations of a virus—not a zombie apocalypse.
R Matthew Chico MPH PhD, Nguyen Tien Huy MD PhD
London School of Hygiene and Tropical Medicine, Nagasaki University School of Tropical Medicine and Global Health
March 17, 2020
Conflict of Interest:
COVID-19 symptoms and viral shedding: Implications for testing and self-Isolation
In 10 weeks of time, COVID-19 has spread from the Hubei Province in Central China to 110 countries, prompting the World Health Organization to declare the outbreak a global pandemic in an acknowledgment that the novel coronavirus threatens to impact all sectors of every country in the world.Lauer and colleagues contributed importantly to our nascent understanding of COVID-19 in their recent Annals publication regarding the incubation of symptomatic infections. The mean period is 5.1 days (95% CI, 4.5 to 5.8 days), an estimate based on analyses of 181 confirmed cases spanning 24 countries and regions outside mainland China, and 25 provinces within mainland China (1). Thus, under the best of circumstances, the average person will seek diagnosis in five days of exposure, with results available two days later.Wölfel and colleagues have added an equally valuable piece to the COVID-19 puzzle in a non-peer-reviewed report (2). Nine patients in Germany, for whom the time of exposure to an index case of SARS-CoV-2 was known, provided biological samples for virology testing. Viral loads in the upper respiratory tract were detected among the first samples collected 48 hours from the onset of symptoms and peaked before day five. Viral concentrations were 1000 times higher than those observed in Hong Kong during the 2004 outbreak of SARS, a related coronavirus (3). Compared to SARS, the viral concentrations of COVID-19 have made contact tracing difficult, particularly in Western countries with highly itinerant populations. Regardless, diagnostic testing remains vital to estimating COVID-19 case-fatality rates, identifying and responding to emerging hotspots, and tailoring medical care at the individual level. Within this context there is now a clear rationale for prioritizing self-isolation of the elderly and immunocompromised for an extended period of time, and promoting social distancing behavior for everyone else. Whether or not lower-risk population groups exposed to SARS-CoV-2 infection will end up developing related IgG, IgM, IgA antibodies and reduce the risk of exposure to groups most at risk of mortality, individuals who acquire immunological defenses will be better able to provide social support to the masses in self-isolation. These are among the most warranted measures now as we bide our time for a deployable COVID-19 vaccine 12 to 18 months from now. References1. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of Internal Medicine. 2020.2. Woelfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Mueller MA, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. medRxiv. 2020:2020.03.05.20030502.3. Poon LL, Chan KH, Wong OK, Cheung TK, Ng I, Zheng B, et al. Detection of SARS coronavirus in patients with severe acute respiratory syndrome by conventional and real-time quantitative reverse transcription-PCR assays. Clinical chemistry. 2004;50(1):67-72.
Cynthia L. Gong, PharmD, PhD,1 Nadine K. Zawadzki, MPH,2 Roy S. Zawadzki,3 Sang K. Cho, PharmD, MPH, PhD,2 Joel W. Hay, PhD2
1Children’s Hospital Los Angeles, University of Southern California, 2Schaeffer Center for Health Policy & Economics, University of Southern California, 3California Polytechnic San Luis Obispo
March 20, 2020
Optimizing Policy in Response to COVID-19
Lauer et al. report the infection rates of COVID-19, with a median incubation time of 5.1 days (95% CI: 4.5-5.8). Though COVID-19 has been declared a global pandemic, social distancing measures to reduce infections will likely have a far greater cost in economic productivity and welfare than this virus will. Extreme, hasty lockdown measures in several countries (e.g. United States, Italy, and China) have effectively halted global, regional, and local economies. Officials have attributed the slowing epidemic in China and elsewhere to such lockdown measures; yet in South Korea, where widespread testing has been most successfully implemented, cases have slowed through traditional case-contact tracing rather than social distancing, which is not effective unless implemented immediately and aggressively. We estimated country-specific logistic growth curves as functions of time from Day Zero (when the cumulative number of reported cases surpasses 100)2 using linear models and ridge regression with leave-one-out cross-validation, estimating Hubei Province separately from the rest of China. Cumulative case curves are similarly shaped among all countries with growth rates lying between those for Hubei and South Korea. While case and fatality reporting in different countries may be subject to differential reporting biases, they are unlikely time-varying. All countries reporting cases 25+ days after Day Zero have demonstrated rapid declines in new cases by Day 25, with growth rates in all countries declining by Day 15. (https://rpubs.com/nzawadzki/covid19-by-country, https://drive.google.com/file/d/1LX2IamvOebtg7Xan9nIvKJ-zVAqbVQlr/view?usp=sharing).Each 1% increase in unemployment corresponds to ~4000 additional deaths per year. Based on these curves, global cumulative cases are unlikely to exceed 500,000 or deaths 50,000, regardless of measures taken. Financial markets have lost >$15 trillion, resulting in more lives lost from panic and economic disruption than gained from social distancing and economy shutdown, at a cost of ~$300 million per life.References Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020. Kuhn A. South Korea's Drive-Through Testing For Coronavirus Is Fast — And Free. Online: NPR; 2020. Available: https://www.npr.org/sections/goatsandsoda/2020/03/13/815441078/south-koreas-drive-through-testing-for-coronavirus-is-fast-and-free Maharaj S, Kleczkowski A. Controlling epidemic spread by social distancing: do it well or not at all. BMC Public Health. 2012;12:679. Hastie T. cv.glmnet - Cross-Validation for Glmnet. RDocumentation. Online: R. Available: https://www.rdocumentation.org/packages/glmnet/versions/3.0-2/topics/cv.glmnet Roelfs DJ, Shor E, Davidson KW, Schwartz JE. Losing life and livelihood: a systematic review and meta-analysis of unemployment and all-cause mortality. Soc Sci Med. 2011;72(6):840-54.
Lauer SA, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020;:. [Epub ahead of print 10 March 2020]. doi: https://doi.org/10.7326/M20-0504
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