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The incubation period of an infectious disease describes the selection bias during the exponential phase of an epidemic [11],
time delay between infection and onset of illness. Incubation determination of illness onset by the predetermined syndromic
periods can vary from one individual to another for various definitions [12], transmission occurring in different settings [11],
reasons including the difference in pathogen transmission and statistical methods and underlining assumptions [10] would
route, the dose of exposure to a pathogen, and the functionality have influenced estimation of the incubation period.
of the host immune system. Incubation periods are often char- Here, we reviewed published estimates of the incubation pe-
acterized by parametric probability distributions such as the riod distribution with a particular interest in the methodology
log-normal, Weibull, and gamma distributions. Coronavirus applied and potential biases that might have affected the esti-
disease 2019 (COVID-19) was first detected in China in mated mean and the right-hand tail measure of the incubation
December 2019 and rapidly spread worldwide, causing a global period distribution.
pandemic with >1.9 million deaths by 13 January 2021. The in-
cubation period distribution of COVID-19 has been a critical METHODS
epidemiological parameter in characterizing the transmission
This systematic review and meta-analysis followed the check-
dynamics, particularly the role of presymptomatic transmission
list of the Preferred Reporting Items for Systematic Reviews and
[1–4] and determination of the quarantine period for persons
Meta-Analyses (PRISMA) guidelines [13].
who might have been exposed to infection [5, 6].
A number of studies have reported estimates of the incubation Search Strategy and Selection Criteria
period distribution, with quite considerable variability between Articles reporting estimates of the incubation period distri-
studies [7, 8]. However, a number of issues can complicate esti- bution of COVID-19 were extracted from the database of
mation of the incubation period distribution and lead to partic- Medline (PubMed; US National Library of Medicine, Bethesda,
ular biases. First, data on the time of infection or exposure are Maryland) with the publication date between 1 February 2020
typically interval-censored rather than exactly known [9, 10], and and 25 September 2020. The following search strategy was used
the probability of infection over time within an exposure interval to search in “All Fields” of PubMed:
may not follow a uniform distribution [4]. Furthermore, the
1. “incubation period”
2. “coronavirus” OR “nCoV” OR “COVID” OR “COVID-19”
Received 15 January 2021; editorial decision 22 May 2021; published online 12 June 2021. OR “2019-nCoV” OR “2019 novel coronavirus” OR “nCoV-
Correspondence: P. Wu, School of Public Health, Li Ka Shing Faculty of Medicine, The
University of Hong Kong, 7 Sassoon Road, Pokfulam, Hong Kong (pengwu@hku.hk). 2019” OR “SARS-CoV-2” OR “Wuhan pneumonia”
Clinical Infectious Diseases® 2021;XX(XX):0–0 3.
(“2020/02/01”[Date - Publication]: “2020/09/25”[Date
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
- Publication])
DOI: 10.1093/cid/ciab501 4. #1 AND #2 AND #3
to a few months in later 2020 (Figure 3A). The estimates of used to estimate the 95th percentile (Supplementary Table 2).
the mean incubation period appeared to be longer for studies The pooled median of the point estimates of the 95th percen-
using data collected in a later period (Figure 2A). The pooled tile of the incubation period was 12.5 days (range, 3.2–18.3).
estimate of mean incubation periods before the epidemic peak Similar to the mean incubation period, lower estimates of the
in China was 5.2 days (9 studies; 95% CI, 4.8–5.7; I2 = 56.5%), 95th percentile were reported in the early phase of the epi-
significantly lower than the pooled estimate for studies con- demic compared to the later phase of the epidemic in China
ducted after the peak (18 studies; 7.2 days [95% CI, 6.6–7.8]; (Figure 3D), with the pooled estimate of 95th percentile to be
I2 = 89.5%) (Figure 3B, Figure 3C). We also identified an asso- 11.0 days (5 studies; 95% CI, 9.9–12.0; I2 = 0.0%) before peak
ciation between the choice of parametric distribution and the and 14.6 days (7 studies; 95% CI, 13.7–15.5; I2 = 66.9%) after
estimated mean incubation period (Figure 4B). The shortest peak. Figure 4D shows variations in the 95th percentile with
estimate of the pooled mean incubation period was from different distributional assumptions. Pooled estimates of the
log-normal (9 studies; 5.9 days [95% CI, 5.1–6.7]; I2 = 81.0%), 95th percentile were 12.6 days (7 studies; 95% CI, 11.2–14.0;
followed by gamma distribution (6 studies; 6.5 days [95% CI, I2 = 61.7%) and 14.1 days (5 studies; 95% CI, 12.3–15.8;
4.9–8.1]; I2 = 94.4%), normal distribution (11 studies; 6.7 days I2 = 87.8%) for estimates based on log-normal distribution and
[95% CI, 6.0–7.3]; I2 = 89.8%), and Weibull distribution (6 Weibull distribution, respectively. Our analyses on individual
studies; 7.0 days [95% CI, 5.8–8.2]; I2 = 93.3%). Similar vari- case data available for Singapore and Tianjin produced similar
ations were identified from an analysis of individual case data observations (Supplementary Figure 2).
collected from Singapore and Tianjin (Supplementary Figures The meta-regression analyses were conducted based only
1 and 2). on the data collected from China, which allowed us to ex-
We identified 34 estimates of the 95th percentile of the in- amine the potential variations in the reported incubation
cubation period distribution. The mid-dates of study period periods before and after the epidemic peak. In total, 27 and
for these studies were between 11 January 2020 and 5 March 12 estimates of the mean and 95th percentile were included
2020, with 11 (32.4%) estimates calculated before the local epi- into the analysis after excluding the estimates from other
demic peak. Distributions of log-normal (10 [29.4%]), gamma territories (5 and 13 estimates for mean and 95th percen-
(5 [14.7%]), Weibull (7 [20.6%]), and normal (12 [35.3%]) were tile, respectively), without reporting the standard deviation,
Figure 2. Estimates of the incubation period for coronavirus disease 2019 from selected studies by type of measure. A, Forest plot of reported mean (dots) estimates of the
incubation period with 95% confidence intervals (CIs) (bars) ordered by mid-date of the study period. B, Forest plot of reported median (triangles) estimates of the incubation
period with 95% CIs (bars) ordered by mid-date of the study period. C, Boxplot of reported mean and median estimates of the incubation period. Citations in panels A and B
corresponds to the reference numbers in Supplementary Materials.
standard error, or 95% CI (1 and 8 estimates), and an ob- We examined the estimates from 4 studies with the mid-point
vious outlier (1.8 days and 3.2 days for the mean and 95th of the study period before the epidemic peak characterizing
percentile). Table 1 shows that the estimates of the mean the incubation period with gamma distributions to explore
and the 95th percentile after the epidemic peak were sig- possible sampling bias in early stage of pandemic. The pooled
nificantly higher than estimates before the peak. Compared mean incubation period from these 4 studies was 5.4 days
to studies using log-normal distribution, no significant dif- (95% CI, 4.4–6.5). If allowing for an exponential growth rate
ferences in the estimates were identified for studies using to be 0.10 [5], the corrected mean incubation period would be
either gamma, Weibull, or normal distribution. 6.4 days (95% CI, 5.2–7.6) (Figure 5). A higher growth rate was
associated with a greater underestimation of the mean incu- between 11 and 14.6 days. Notably, we identified a bias towards
bation period in estimates without a correction (Figure 5 and shorter estimates of the incubation period in the early stage of
Supplementary Materials). the pandemic while case numbers were rising exponentially,
which was also indicated by the temporal patterns of the incu-
bation period estimated throughout the epidemic based on in-
DISCUSSION
dividual case data from Singapore and Tianjin (Supplementary
We reviewed 72 studies on the incubation period distribution Figure 1).
of COVID-19, 62 of which were based on data collected from Variation in estimates of the mean incubation period were
China. The pooled estimates from our analysis indicated that expected to result from bias in case ascertainment that people
the mean incubation period of COVID-19 was likely to fall with shorter incubation periods were more likely to be included
between 5.2 and 7.2 days, and the 95th percentile would be in the growing stage of the pandemic, which could be corrected
Study period
Before peak 9 0 Referent 5 0 Referent
After peak 18 1.95 (.92–2.98) 7 3.4 (1.62–5.17)
Approach
Log-normal 7 0 Referent 7 0 Referent
Gamma 5 .61 (–.80 to 2.02) … …
by observing exposure to infection and the development of subsequent analyses and to support health policies [20]. Our
symptoms in a cohort of individuals over the epidemic [11]. In proposed correction for sampling bias might be able to pro-
addition, in the early stage of the pandemic, published studies vide a more accurate estimate of the incubation period from
tended to include patients with well-characterized informa- data collected in the early phase of an epidemic when infections
tion, such as seriousness of infection or exposure details, which are increasing exponentially. Correcting for the growth rate
might lead to a underestimation of the incubation period [19]. can account for the proportion of cases with longer incubation
Other factors could also contribute to the difference, including periods who are relatively less likely to be included in early data
publication bias, overrepresentation of milder cases, and dif- (Supplementary Materials and Figure 5). Shorter estimates of
ferent ways of establishing exposure windows. Few studies ac- the incubation period could also be related to exposure to a
counted for such potential bias in estimation of the incubation high viral load or virus strains with higher virulence [16].
period. The earliest, perhaps biased, estimates of the incubation One of the applications of the incubation period distribution
period distribution have been, however, widely used in many is in determining the time period of quarantine for exposed in-
dividuals. Our study found that the pooled estimates of the 95th
percentile of the incubation period before and after the epi-
demic peak were 11.0 and 14.6 days, respectively. This indicated
that a quarantine period of 14 days could capture at least 95% of
infected individuals who would develop symptoms.
The distinction between the incubation period and the latent
period implies that the latent period of COVID-19 is gener-
ally expected to be shorter than the incubation period because
of the occurrence of presymptomatic transmission [3, 21, 22].
A number of estimates of the latent period have been published,
with the reported means ranging from 2.6 to 3.3 days [23, 24] or
from 1.88 to 7.4 days before symptom onset [3, 22]. The earlier
shedding of virus than symptom onset made it critical to test
exposed individuals during quarantine so that asymptomatic
cases could also be identified [25–28]. Laboratory testing before
exit from 2-week quarantine may identify some infected persons
with the incubation period >14 days. Johansson et al estimated
that the residual risk of transmission after a 10-day quarantine
would be as low as 0.3% for asymptomatic individuals with a
negative laboratory test result at the last day of quarantine [29].
Quilty et al estimated that the transmission-potential averted
Figure 5. Prospective correction for the incubation period estimates during the
early phase of the pandemic. For given estimates of incubation period as gamma rates were similar between 14 days of quarantine without poly-
(mean [standard deviation]) in the different studies during the exponential phase of merase chain reaction test and 7 days of quarantine with a neg-
the epidemic, the corrected pooled mean (blue line) and 95% confidence interval ative exit test [30]. On 2 December 2020, the US Centers for
(shaded area) are presented for different possible growth rates (r = 0.00–0.20). The
scenario r = 0 indicates no correction for growth rate and the respective suggested Disease Control and Prevention updated the recommendation
corrections can be attained based on the exponential growth rates, r > 0. on the quarantine period, allowing asymptomatic individuals