key: cord-0709872-cfn3ywb4 authors: Dhouib, Wafa; Maatoug, Jihen; Ayouni, Imen; Zammit, Nawel; Ghammem, Rim; Fredj, Sihem Ben; Ghannem, Hassen title: The incubation period during the pandemic of COVID-19: a systematic review and meta-analysis date: 2021-04-08 journal: Syst Rev DOI: 10.1186/s13643-021-01648-y sha: 0abfbcbbefb6afbb83f6186022aa6f94977d8694 doc_id: 709872 cord_uid: cfn3ywb4 BACKGROUND: The aim of our study was to determine through a systematic review and meta-analysis the incubation period of COVID-19. It was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Criteria for eligibility were all published population-based primary literature in PubMed interface and the Science Direct, dealing with incubation period of COVID-19, written in English, since December 2019 to December 2020. We estimated the mean of the incubation period using meta-analysis, taking into account between-study heterogeneity, and the analysis with moderator variables. RESULTS: This review included 42 studies done predominantly in China. The mean and median incubation period were of maximum 8 days and 12 days respectively. In various parametric models, the 95th percentiles were in the range 10.3–16 days. The highest 99th percentile would be as long as 20.4 days. Out of the 10 included studies in the meta-analysis, 8 were conducted in China, 1 in Singapore, and 1 in Argentina. The pooled mean incubation period was 6.2 (95% CI 5.4, 7.0) days. The heterogeneity (I(2) 77.1%; p < 0.001) was decreased when we included the study quality and the method of calculation used as moderator variables (I(2) 0%). The mean incubation period ranged from 5.2 (95% CI 4.4 to 5.9) to 6.65 days (95% CI 6.0 to 7.2). CONCLUSIONS: This work provides additional evidence of incubation period for COVID-19 and showed that it is prudent not to dismiss the possibility of incubation periods up to 14 days at this stage of the epidemic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13643-021-01648-y. Since December 2019, the world is facing the pandemic of COVID-19. As of December 8, 2020, a total of cumulative confirmed cases were estimated at more than 68 million and 1.5 million cumulative deaths with a case fatality rate of 2.28% [1, 2] . While awaiting a vaccine, massive public health interventions such as social awareness, social distancing, isolation, quarantine, contact tracing, targeted screening, and border controls have been implemented nationally and globally to limit transmissibility and contain the epidemic since late January [3] [4] [5] [6] . The incubation period, one of the key epidemiological parameters, is essential to epidemiological case definition, to determine the appropriate duration of quarantine and to estimate the size of the epidemics. Therefore, it was rapidly being studied from incoming case reports as the epidemic continues. Several studies have confirmed that cases are infectious during the asymptomatic period (latency period) prior to onset and that disease transmission may be carried out [7] [8] [9] [10] . Up to this point, the quarantine and isolation duration of exposed or suspected cases is set at 14 days, which is the longest incubation time expected based on initial observations of SARS-CoV-2 and similarity to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) [11] . The distribution of the incubation period in most of the literature is either described through a parametric model or its empirical distribution based on the observed incubation period from the contact-tracing data (specific data indicating the time of exposure). However, the contact-tracing data are challenging and expensive to obtain, and their accuracy can be highly influenced by recall bias. Therefore, previous population dynamics studies tend to make assumptions about the distribution of the incubation period without using the observed data called modeling studies, and we are talking here about an estimate of the incubation period. Furthermore, estimating and standardizing the incubation period of COVID-19 may vary depending on climate [12] , on age or the genetic of the individuals, their pathologies, or their treatment like the long-term use of glucocorticoids which might cause atypical infections and a long incubation period [13] . Thus, a specific maximum duration of the incubation period is needed to answer if the 14-day quarantine is sufficient to protect against the spread of the pandemic. In this systematic review and meta-analysis, we tried to identify studies that recruited symptomatic patients, regardless of sex or age diagnosed with COVID-19, and calculated or estimated the incubation period between December 2019 and December 2020. The protocol for this review was registered with PROS-PERO (international prospective register of systematic reviews) under the number CRD42020196347 (https:// www.crd.york.ac.uk/prospero/). This systematic review was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to study the length of incubation period during the COVID-19 pandemic. Criteria for eligibility were all published populationbased primary literature dealing with incubation period of COVID-19, since December 2019. We included fulltext publications and excluded all articles not accepted or peer reviewed, not written in English, editorials, perspective, letter to the editor, review, article info, and comments. We only took articles that used RT-PCR for the diagnosis of COVID-19. Since randomized controlled trials (RCTs) do not apply to this topic, only observational studies with no limit on the number of participants were included. There were no limitations given the types of outcome measures: we accepted all documents that presented results even without a statistical parameter of variability. We included individuals with a confirmed diagnosis of COVID-19 regardless of the severity of symptoms or associated comorbidities. There were no age, gender, or ethnicity restrictions. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)). We also excluded studies including populations with mixed viral diseases (e.g., COVID-19 plus influenza). The incubation period was defined as the amount of time between the exposure to SARS-CoV-2 and the onset of symptoms [14] . Estimated and calculated incubation period 1. Incubation periods were calculated from observed data based on specific dates indicating the time of exposure. Measures of central tendency were ranges, mean, and median with appropriate dispersion parameters (interquartile range (IQR) and standard deviation (SD)). 2. Incubation periods were estimated on incomplete data or imprecise exposure time using several models of distribution such as log-normal, Weibull, and Gamma distribution [15, 16] . They were presented by the mean and its 95% confidence interval (95% CI) with percentiles of the distribution in some studies. OR 2020[PDAT]))). No filter was applied. The research was also conducted on Science Direct through its advanced research (only the research article using COVID-19 and the incubation period in the title, abstract, or keywords specified by the author). The literature search was completed on 01/12/2020. Selection of studies and data extraction The references were managed using the Zotero software. Firstly, and after exclusion of duplicates, all titles and abstracts of publications identified through the initial primary search were single reviewed for relevance. Secondly, the final selection of the articles was based on the full texts of papers by retrieving and checking for relevance by two authors (WD, AI) independently of each other, with referral to MJ in the case of discordant opinions. Studies were excluded if they were off topic or if they gave no number or statistics. One article was retracted from Medline during the process of final selection. We documented the study selection process in a flow chart and showed the total numbers of retrieved references and the numbers of included and excluded studies ( Fig. 1) . One review author WD performed all data extractions. Two other review authors (AI and MJ) verified the accuracy and the plausibility of extractions. All authors participated in quality assessment, level of evidence, and grades of recommendations. DW and AI independently reviewed all studies, with disagreements resolved by referral to MJ. The following bibliometric, epidemiological data were extracted: authors, study design, country or geographical region, period of study, sample size, data and source collection, general characteristics of the studied population (age, sex ratio), exposure history, and duration of incubation period. The meta-analysis was based on the mean of the distributions either in observed or estimated lognormal distribution data. The meta-analysis included all studies that reported the mean with its SD of the observed incubation period or the mean and corresponding CI of the normal log distribution. Excluded studies where those representing outcome reporting bias. The selection of studies to include in the metaanalysis was conducted by the primary author WD. Quality assessment was done according to recommendation of "Quality Assessment Tool for Quantitative Studies" developed in Canada by the Effective Public Health Practice Project (EPHPP) [17] . Once the assessment is fulfilled using a number pre-determined criteria, each examined practice receives a mark ranging between "strong," "moderate," and "weak" in three categories (study design, data collection practices, and selection bias). After discussing the ratings and resolving any discrepancy, the global rating for each paper was according to the sum of "weak" ratings given to the three categories (1: strong=0 "weak"; 2: moderate=1 "weak"; and 3: weak=≥2 "weak") (Additional file 1). Risk Level of evidence and grades of recommendations were assessed according to the Scottish Intercollegiate Guidelines Network (SIGN) [18] . Levels of evidence were graded into 8 levels from 1++ (high quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias) to 4 (expert opinion). There were 4 grades of recommendations (A, B, C, and D) based on the results of the level of evidence. D is given if the evidence level was 3 or 4 or extrapolated from studies rated as 2+ [18] . A random effects meta-analysis was conducted in the Open Meta Analyst software [19] , of the calculated and estimated mean of the log-normal distribution. Forest plots were produced using the same package. Heterogeneity between the studies was assessed using both the I 2 statistic with a cutoff of 50% and the χ 2 test with P-value <0.10 and investigated by conducting subgroup analyses of the data set following these moderator variables: population of studies (Chinese or not), severity (hospitalized or not), sex ratio (> or < 1), study quality, and method of calculation (estimated or calculated). We identified 117 records through Medline and Science Direct database searches. After removing 3 duplicates, we screened 114 records based on their titles and abstracts, leaving 48 full manuscripts to be assessed for eligibility ( Fig. 1) . As a result of this assessment, 42 studies met the inclusion criteria. Over the 42 observational studies, the quality assessment gave 9 strong, 19 moderate, and 14 weak studies (Additional file 1). Most of the studies had a retrospective data collection; 10 had a prospective one [7] [8] [9] [20] [21] [22] [23] [24] [25] [26] . The sampling methods and sample size recorded varied substantially across studies. In some cases, entire provinces or villages were selected [8, 9, 20, [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] whereas in others the focus was on serial cases or family clusters [7, 8, 24, [38] [39] [40] [41] [42] , hospitals, and laboratory [43] [44] [45] [46] [47] [48] [49] [50] . Almost studies were done in China (30 studies), including a study of around 8579 people in 30 provinces [23] . Four studies was conducted in Korea [9, 28, 34, 51] , three in Singapore [21, 48, 52] , one in France [41] , one in Brunei [32] , one in Argentina [33] , one in Saudi Arabia [53] , and two in Germany [37, 42] . The period of all studies was between January and May 2020 ( Table 1) . All the 42 observational studies had the third level of evidence (non-analytic studies) with a grading D of recommendation. Most of study had the risk of recall bias (Fig. 2) . Based on studies calculating incubation period for SARS-CoV-2 The median incubation period was calculated in 17 studies ranging from 2 to 12 days with an IQR lower bound of 2 days and higher bound of 14 days. In 9 studies, the mean was ranging from 3.9 to 8.98 days. The total incubation period ranged in 9 studies from 0 to 26 days. One study was restricted to pediatric patients infected with SARS-CoV-2 from 7 months to 17 years old. The average incubation period was 8 days ranged from 1 day to 13 days [43] (Table 2) . The log-normal distribution was the best fitting to the data in 7 studies with an estimated mean ranging from 5.0 to 7.4 (95% CI, 2 to 20 days) ( Table 3 ). The median was estimated in 9 studies and had a maximum value of 7.2 (95% CI, 6.4 to 7.9 days) [58] . The estimated 95th percentile of the distribution had a maximum value of 16.32 days. The maximum 97.5th and 99th percentile of the distribution was 11.5 days and 20.4 days respectively (Table 3) . The estimated mean incubation period obtained from the included studies and the pooled mean are presented in Fig. 3 . Out of the 10 included studies in the meta-analysis, 8 were conducted in China, 1 in Singapore, and 1 in Argentina. The pooled mean 3.0 Cluster incubation period was 6.2 (95% CI 5.4, 7.0) days. Heterogeneity testing (I 2 = 77.1%; p < 0.001) revealed notable differences among the included studies in the meta-analysis. Moderator variables were analyzed to identify and eliminate the observed heterogeneity: population of studies, severity, sex-ratio, study quality, and method of calculation ( Table 4 ). The heterogeneity was decreased when we included the study quality and the method of calculation used as moderator variables (I 2 0%). The mean incubation period ranged from 5.2 (95% CI 4.4 to 5.9) to 6.65 days (95% CI 6.0 to 7.2) (Fig. 3 ). This review includes 42 studies done predominantly in China showing a mean and median incubation period of maximum 8 days and 12 days respectively. The pooled mean incubation period for COVID-19 is 6.2 (95% CI 5.4, 7.0) and may vary depending on population of studies, severity, sex-ratio, study quality, and method of calculation. In various parametric models, the 95th percentiles were in the range 10.3-16 days, which was not consistent with the first WHO reports [61] . While it was difficult to estimate the right hand tail of the incubation period distribution based on small sample sizes, the highest 99th percentile would be as long as 20.4 Fig. 2 Overall and detailed risk of bias assessment among the 42 studies days, and this indicates that long incubation periods are possible. Lauer et al. [56] estimated that 101 out of 10, 000 cases (99th percentile=482) would develop symptoms after 14 days of active monitoring or quarantine. Wang et al. [57] reported that about 7.45% patients were overestimated with longer than 14 days of incubation periods. Although many studies did not match with the inclusion criteria in our review, they are worthy to be mentioned. In a research letter studying serial cases of 6 patients infected with SARS-CoV-2 in China, Bai et al. reported that the incubation period of patient 1 was 19 days [63] . Based on 175 case details reported by 64 web pages between January20, 2020, and February 12, 2020, Leung estimated a mean of 7.2 (95% CI 6.1 to 8.4) with a 95th percentile of the Weibull distribution of 14.6 days (95% CI, 12.1 to 17.1) [64] . On the other hand, in the beginning of the pandemic of COVID-19, some studies found that there is no observable difference between the incubation time for SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) [11] . In our results, studies with contact tracing or exposure history of close contact showed a range of incubation period not exceeding 14 days [8, 38, 40, 41] . In fact, potential direct transmission could be related to a higher [30] . These results strengthen the hypothesis that a higher infecting dose could have been transmitted by the index case leading to a shorter incubation period compared with cases associated with "indirect" transmission. In our study, there was considerable heterogeneity investigated with subgroup analysis. Several articles have shown that the incubation period differs between individuals according to their age or sex. Tan et al. showed that age-specific mean incubation periods were statistically significantly different across different age categories. The longest was observed among those aged 70+ (7.56 days, 95% CI 5.31-9.80) while the shortest was among those aged 60-69 years (4.69 days, 95% CI 3.86-5.52) and <30 years (4.95 days, 95% CI 4.31-5.58) [48] . However, Qin et al. concluded that there is no evidence that the incubation time depends on age [35] . Systematic reviews and meta-analyses conducted from 1 December 2019 to 11 March showed that the pooled incubation period mean was 5.68 (99% CI: 4.78, 6.59) days with heterogeneity testing (I 2 = 98.4%) [66] . As in our findings, this heterogeneity test revealed notable differences among the included studies. On the other hand, and based on the log-normal distribution, McAloon et al. [67] found in a meta-analysis conducted from December 1, 2019, to April 8, 2020, a mean of 5.8 days (95% CI 5.0-6.7) for the corresponding incubation period. However, our results with an estimated incubation mean of 5.2 (95% CI, 4.4-5.9) were more reliable since the heterogeneity test was zero. Our study has some notable limitations. First, in most studies, the data were collected retrospectively, resulting in a recall bias (uncertain exact dates of exposure) and some missing data that would inevitably influence our assessment. Second, due to urgent timeline for data extraction and analysis, many studies have estimated the incubation period in a limited case number in a short period of time, which necessitates the cautious interpretation of the generalizability of our findings. The numbers were too small to detect systematic differences in incubation time with age or sex. Third, not all studies Fig. 3 Forest-plot for mean incubation period in days (except Tian et al. [44] ) paid attention to asymptomatic patients, so our review may represent an erroneous incubation period. Although there is interest on asymptomatic transmission, we were unable to address this point in our review, and further studies should be done to better understand disease transmissibility of asymptomatic cases. This work provides additional evidence of incubation period for COVID-19 and showed that it is prudent not to dismiss the possibility of incubation periods up to 14 days at this stage of the epidemic. As the epidemic continues, it remains important to collect more information on incubation periods through longitudinal studies with more patients so that we can conduct subgroup analysis and better understand the transmissibility of. The online version contains supplementary material available at https://doi. org/10.1186/s13643-021-01648-y. Additional file 1:. Quality assessment of the included studies. Weekly operational update on COVID-19 CMMID nCoV working group. 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Authors' contributions WD: conceptualization, research literature, and writing-original draft. IA and JM: research literature and quality assessment. NZ, RG, SBF: contributor in writing the manuscript. HG: revision of all manuscript. All authors read and approved the final manuscript.