key: cord-0984810-itda59dg authors: Elias, Christelle; Sekri, Abel; Leblanc, Pierre; Cucherat, Michel; Vanhems, Philippe title: Incubation period of COVID-19: a meta-analysis date: 2021-02-03 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.01.069 sha: c5731ae63a7679b49337e683de27e52f7e51621f doc_id: 984810 cord_uid: itda59dg Objectives Valid measurement of the SARS-CoV-2 incubation period is needed for case definitions and for adapting appropriate isolation measures but is challenging in an emergency context. Our objective was to systematically review recent literature of reported estimates of the distribution of incubation period of SARS-CoV-2 with the aim of describing the distribution and its variability and dispersion through meta-analysis. Methods A systematic review search was carried out up to January 10, 2021 of all identified references available reporting the SARS-CoV-2 incubation period. Individual mean and standard deviation were used to produce the pooled estimate. Sources of heterogeneity were explored by age, gender and study design using a meta-regression. Results In total, 99 studies were eligible for analysis in our meta-analysis. The pooled estimate of the mean incubation period across the studies was 6.38 days, 95% CI [5.79; 6.97]. Conclusion The mean incubation period will help for identification of time of exposure, but determinants of its variations/range might be explored for potential links with clinical outcome or pathogenic steps at early time of infection. A real time meta-analysis, called the InCoVid Lyon, is proposed on an appropriate website following this initial analysis. Valid measurement of the SARS-CoV-2 incubation period is needed for case definitions and for adapting appropriate isolation measures but is challenging in an emergency context. Our objective was to systematically review recent literature of reported estimates of the distribution of incubation period of SARS-CoV-2 with the aim of describing the distribution and its variability and dispersion through meta-analysis. A systematic review search was carried out up to January 10, 2021 of all identified references available reporting the SARS-CoV-2 incubation period. Individual mean and standard deviation were used to produce the pooled estimate. Sources of heterogeneity were explored by age, gender and study design using a meta-regression. In total, 99 studies were eligible for analysis in our meta-analysis. The pooled estimate of the mean incubation period across the studies was 6.38 days, 95% CI [5.79; 6.97]. The mean incubation period will help for identification of time of exposure, but determinants of its variations/range might be explored for potential links with clinical outcome or pathogenic steps at Introduction COVID-19 is an infectious disease associated with severe acute respiratory syndrome of Coronavirus-2 (SARS-CoV-2) causing lower respiratory tract infections, and responsible for more than two million deaths worldwide [Gisanddata map, 2020]. Incubation period is the interval time elapsed between the moment a person is infected until the onset of the disease. Knowledge of the incubation period is essential for the case definition, management of emerging threats, estimation of the duration follow-up for contact tracing and secondary case detection and the establishment of public health programs aimed at reducing local transmission [Nishiura H, 2012 ]. According to the WHO, SARS-CoV-2 incubation period ranging from 1 to 14 days has been reported [WHO, 2020] . Distribution of the incubation period may vary between individuals as a result of certain determinants such as host factors. There is a need to complete the knowledge on the incubation period distribution of SARS-CoV-2 in order to support effective outbreak investigations. Therefore, the objective was to systematically review recent literature of reported summary estimates of the distribution of incubation period of SARS-CoV-2 through a meta-analysis. The search was carried out from inception to January 10, 2021. Articles or abstracts in languages other than English were excluded. General information on the published article, the study characteristics, and summary measures of the incubation period were gathered. Measures of dispersion as well as data on age and gender distribution were collected where available. All studies reported at least one summary statistic of the incubation period distribution as a mean, median, or range. The unit of measurement was in days. Individual mean and standard deviation were used to produce the pooled estimate. Inverse variance weighting was used for pooling individual estimation of mean, median, 95 th end 97.5 th percentile of the incubation period. Heterogeneity between studies was assessed using I 2 statistics [Higgins JPT, 2002] . Age, gender and study design were considered as candidate explicative covariables. All data analyses were done using R (version 3.6.3). Results of this meta-analysis are shared on the following site: InCoVid-Lyon [Incovid, 2020] . Among all articles, 99 were analyzed (Supplementary appendix 1) . The majority of the studies reported an incubation period from Asian cases. In total, 23 (23.2%) cohorts, 61 (61.6%) case series and 15 (15.2%) modelling studies were gathered, with a median age of 45 years, and a sex ratio greater than 1. The median sample size was estimated at 52 [IQR 20; 161] individuals. Figure 1 shows that the mean incubation period was equal to 6 SARS-CoV-2 appears to be most contagious around the time of symptom onset and infectivity rapidly decreases thereafter to near-zero after about 10 days in mild-moderately ill patients and 15 days in severely-critically ill and immunocompromised patients [Rhee, 2020] . A quarantine period of at least 10 days would be necessary to limit the transmission of the virus from the exposed cases. In the context of nosocomial cases or confined environments (i.e. classrooms in schools or cruise ships), knowing incubation will help for identification of exposed individuals. The incubation time matters to tailor non pharmaceutical public health interventions such as timely isolation, and also for contacts to be traced and quarantined in time. The precise estimation of the incubation period is also relevant for exploring early pathogenetic mechanisms with potential links with the outcome [Vanhems P, 2000 ]. Promptly after its emergence, SARS-CoV-2 was identified to be responsible for human transmission during the incubation period [Jin YH, 2020] . Previous studies have suggested that a short incubation J o u r n a l P r e -p r o o f period could have an impact on the severity of infection caused by coronavirus species [Virlogeux V, 2016 ]. Therefore, more knowledge about the link between the incubation period and the viral load is essential to tailor clinical decision making and assess COVID-19 severity. The need to ascertain an accurate definition of the incubation period has become urgent in order to better define cases and duration of isolation measures. Discrepancies among sources may hamper case detection and the effectiveness of infection control measures. J o u r n a l P r e -p r o o f Quantifying heterogeneity in a meta-analysis A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version Effectiveness of isolation, testing, contact tracing, and physical distancing on reducing transmission of SARS-CoV-2 in different settings: a mathematical modelling study. CMMID COVID-19 working group Incubation period as part of the case definition of severe respiratory illness caused by a novel coronavirus Duration of SARS-CoV-2 Infectivity: When is it Safe to Discontinue Isolation? Incubation time of acute human immunodeficiency virus (HIV) infection and duration of acute HIV infection are independent prognostic factors of progression to AIDS Association between Severity of MERS-CoV Infection and Incubation Period Isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-nCoV) outbreak The authors thank Michelle Grange for editing the manuscript. None declared. None declared. CE and PV conceived and designed the study. PV coordinated the study. CE, AS and PL collected the data. MC and CE conducted data analyses. MC designed the Incovid-Lyon website. All authors contributed to data interpretation, the manuscript draft and approved the final version of the manuscript. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.