Volume 23, Number 5—May 2017
Estimated Incubation Period for Zika Virus Disease
Information about incubation is needed for identifying local and alternative modes of Zika virus transmission. Data from 2015–2016 for 197 symptomatic travelers with recent Zika virus disease indicated an estimated incubation period of 3–14 days. For persons in whom symptoms develop >2 weeks after travel, transmission might not be travel associated.
Zika virus is a mosquito-borne flavivirus transmitted primarily through the bite of infected Aedes spp. mosquitoes. Transmission can also occur by intrauterine, intrapartum, or sexual routes or through accidental exposure in laboratory settings (1–3).
In May 2015, Zika virus disease cases were identified in Brazil, representing the first local transmission in the Americas (4). Subsequently, Zika virus spread rapidly, resulting in >463,000 suspected and laboratory-confirmed cases in the Americas as of June 30, 2016 (5). This rapid expansion highlighted key knowledge gaps, including the incubation period for Zika virus disease. Characterizing the incubation period for Zika virus disease is needed to identify local virus transmission and alternative modes of transmission. To estimate the incubation period, we used data from symptomatic persons who had traveled to an area with ongoing Zika virus transmission and had laboratory evidence of recent infection.
We included in our analysis persons for whom samples were tested at the Centers for Disease Control and Prevention from January 1, 2015, through June 23, 2016, and had evidence of recent Zika virus infection (defined as Zika virus RNA positivity by real-time reverse transcription or Zika or dengue virus positivity by IgM capture ELISA and confirmed by plaque reduction neutralization test with a Zika virus–specific neutralizing antibody titer >10 and Zika virus titer >4-fold higher than dengue virus titer) (6,7). We restricted our analysis to persons who were symptomatic, had known symptom onset date (onset of first symptom), had known travel dates from/to the continental United States, and were probably infected through a mosquito bite. We excluded from analysis those for whom disease was congenital or sexually transmitted and those reporting illness onset >2 months after travel, because of the typically shorter known incubation periods for other flavivirus diseases.
To estimate the incubation period, we first defined the exposure period as either the duration of travel if the person experienced illness after return from travel or the time from beginning of travel to onset of illness if the person became ill during travel (Figure 1, panel A). We then fit various probability distributions in R (https://cran.r-project.org/) by using the dic.fit functions in the coarseDataTools package, which uses methods detailed by Reich et al. (8). We selected the best model by using the Akaike information criterion. In addition to reporting fitted cumulative distribution function and associated 95% CIs, we reported certain quantiles and means. All analyses were conducted by using R.
For our primary analysis, we used all symptomatic persons with evidence of recent Zika virus infection (primary case set). We then performed a secondary analysis of persons with confirmed Zika virus infection and <2 weeks of travel (secondary case set), enabling estimate evaluation by use of more stringent case definition requirements. A confirmed case of Zika virus disease was defined as a sample that was Zika virus RNA positive or Zika or dengue virus IgM positive with neutralizing antibodies against Zika virus only.
We identified 337 persons with evidence of recent Zika virus infection from January 1, 2015, through June 23, 2016. Of these, we excluded 140 (42%) because they did not meet the study criteria (Figure 2). Among the remaining 197 persons, median age was 42 (range 1–81) years, about half (119/197; 60%) were female, and 11 (6%) were pregnant (Table). Median length of travel was 11 (range 2–177) days. The diagnosis of recent Zika virus infection was made by serologic testing for 134 (68%) persons, by molecular testing for 57 (29%), and by molecular and serologic testing for 6 (3%).
The Weibull distribution fit our data best (parameter estimates in Technical Appendix [PDF - 138 KB - 1 page] Table 1 ). For the primary case set, our estimates for the incubation period were median 6.2 (95% CI 5.7–6.6) days (Figure 1, panel B) and mean 6.4 (95% CI 5.7–7.0) days. We estimated that, among persons in whom symptoms would develop, they would develop in 5% by 2.1 (95% CI 1.7–2.4) days and in 99% by 13.6 (95% CI 13.0–14.2) days (Figure 1, panel B; Technical Appendix [PDF - 138 KB - 1 page] Table 2).
Of the 112 (57%) persons who had traveled for <2 weeks, the definition of a confirmed case was met by 79 (71%). The age and sex distributions for these patients did not differ significantly from those of the primary case set (p = 0.67 and 0.44, respectively) (Table). The median length of travel was 8 (range 3–13) days. Zika virus diagnosis was confirmed by serologic testing for 47 (59%) patients, by molecular testing for 31 (39%), and by both methods for 1 (1%).
For patients whose illness met the definition of a confirmed case, we estimated the median incubation period to be 5.8 (95% CI 5.0–6.7) days (Figure 1, panel B; Technical Appendix [PDF - 138 KB - 1 page] Table 2) and the mean to be 6.0 (95% CI 5.2–6.8) days. The quantile estimates (5%–95%) for these patients were similar to those for all travelers; however, among travelers who had traveled <2 weeks and had confirmed Zika virus infection, symptoms developed within 11.8 (95% CI 10.8 –12.9 days) days for 99%, compared with 13.6 days for all travelers.
On the basis of our analysis, we estimate that the incubation period for Zika virus disease is 3–14 days. We expect symptoms to develop within 1 week of infection for 50% and within 2 weeks for 99% of persons. Our estimates for the Zika virus disease incubation period are similar to those reported for other flavivirus diseases (9–12). The incubation period for Zika virus disease has been estimated by Lessler et al., who reported data from 25 patients with variable exposure and laboratory evidence of infection (13). Their estimated median incubation period was similar to ours, 5.9 days, but the upper limit from that study was 18 days, which is 6 and 7 days longer than our estimates for the primary and secondary case sets, respectively. The difference in the upper limit was probably the result of the lower case number and higher variability in travel durations for their cohort.
Our analysis has several limitations. First, all samples were submitted to the Centers for Disease Control and Prevention according to guidance for testing, which recommended testing only persons with symptom onset <2 weeks after travel (14). Evaluating only this population could have biased our estimate toward a shorter incubation period. Second, we considered persons who were Zika virus IgM positive as having recent infection. However, because the duration of IgM after Zika virus infection is not known, we might have included persons who had a prior infection unrelated to their most recent travel. Third, our analysis does not include other modes of transmission, such as sexual, for which the incubation period might differ. Fourth, we cannot be sure that all cases included in the analysis were caused by vector transmission because sexual transmission may have occurred during travel. Last, our primary case set included 11 pregnant women. Data suggest that the immunologic response to Zika virus infection might differ during pregnancy (15); however, in our analysis, incubation periods for pregnant women did not differ qualitatively from those for nonpregnant travelers.
According to our analysis, among Zika virus–infected travelers who will become symptomatic, 99% will experience symptoms within 2 weeks of exposure and 50% within 1 week. Persons for whom symptoms develop >2 weeks after travel and who have laboratory evidence of Zika virus infection should be evaluated for alternative modes of transmission (e.g., sexual transmission) or local vectorborne transmission.
Dr. Krow-Lucal is an Epidemic Intelligence Service Officer with the Arboviral Diseases Branch, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA. Her primary research interests are immunology and infectious disease.
We thank the Zika Virus Response Epidemiology and Laboratory Teams and vectorborne disease surveillance coordinators in state and local health departments for their efforts with collection and sharing of data used in this analysis.
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- Figure 1. Estimated distribution of incubation period in days since infection for persons with evidence of recent Zika virus disease. A) Representation of individual interval censored travel data based on time...
- Figure 2. Persons with Zika-like symptoms and positive test results for Zika virus infection identified from samples received and tested for Zika virus infection at the Centers for Disease Control and...
- Table. Demographics and travel data for Zika virus disease patients, United States, January 1, 2015, through June 23, 2016
- Technical Appendix. Parameter and incubation period quantile estimates for persons with confirmed Zika virus disease and for all persons with Zika virus disease, United States, January 1, 2015, through June 23,... 138 KB
Suggested citation for this article: Krow-Lucal ER, Biggerstaff BJ, Staples JE. Estimated incubation period for Zika virus disease. Emerg Infect Dis. 2017 May [date cited]. http://dx.doi.org/10.3201/eid2305.161715
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J. Erin Staples, Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, 3156 Rampart Rd, Mailstop P02, Fort Collins, CO 80521, USA
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