Incidence of Dengue Virus Infection in Adults and Children in a Prospective Longitudinal Cohort in the Philippines

Background The mean age of dengue has been increasing in some but not all countries. We sought to determine the incidence of dengue virus (DENV) infection in adults and children in a prospective cohort study in the Philippines where dengue is hyperendemic. Methodology/Principal Findings A prospective cohort of subjects ≥6 months old in Cebu City, Philippines, underwent active community-based surveillance for acute febrile illnesses by weekly contact. Fever history within the prior seven days was evaluated with an acute illness visit followed by 2, 5, and 8-day, and 3-week convalescent visits. Blood was collected at the acute and 3-week visits. Scheduled visits took place at enrolment and 12 months that included blood collections. Acute samples were tested by DENV PCR and acute/convalescent samples by DENV IgM/IgG ELISA to identify symptomatic infections. Enrolment and 12-month samples were tested by DENV hemagglutination inhibition (HAI) assay to identify subclinical infections. Of 1,008 enrolled subjects, 854 completed all study activities at 12 months per-protocol undergoing 868 person-years of surveillance. The incidence of symptomatic and subclinical infections was 1.62 and 7.03 per 100 person-years, respectively. However, in subjects >15 years old, only one symptomatic infection occurred whereas 27 subclinical infections were identified. DENV HAI seroprevalence increased sharply with age with baseline multitypic HAIs associated with fewer symptomatic infections. Using a catalytic model, the historical infection rate among dengue naïve individuals was estimated to be high at 11–22%/year. Conclusions/Significance In this hyperendemic area with high seroprevalence of multitypic DENV HAIs in adults, symptomatic dengue rarely occurred in individuals older than 15 years. Our findings demonstrate that dengue is primarily a pediatric disease in areas with high force of infection. However, the average age of dengue could increase if force of infection decreases over time, as is occurring in some hyperendemic countries such as Thailand.


Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported The introduction states: "Yet, very few prospective longitudinal cohort studies undergoing active surveillance have been conducted in adults to assess overall incidence and disease burden [18,19]; and even fewer have evaluated dengue incidence and relative proportion of subclinical infections in adults and children within the same cohort." Objectives 3 State specific objectives, including any prespecified hypotheses The introduction states: "In order to elucidate the incidence of symptomatic and subclinical DENV infections in adults as well as children, we conducted a prospective longitudinal cohort study in Cebu City, Philippines, among subjects of all ages ≥6 months."

Study design 4
Present key elements of study design early in the paper This was presented early in the Methods section under the sub-section "Prospective Cohort." Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection

This was described in the Methods section under the sub-sections "Study
Location" and "Prospective Cohort." Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up.

This was described in the Methods section under the sub-sections "Prospective
Cohort" and "Active Surveillance." (b) For matched studies, give matching criteria and number of exposed and unexposed Not applicable.

Variables 7
Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable

This was described in the Methods section under the sub-section "Prospective
Cohort." Laboratory definitions were described in the Methods section under the sub-section "Laboratory Assays." Symptomatic DENV infections were defined as illnesses with reported history of fever with specific laboratory criteria.
Subclinical infections were defined as those without reported history of fever but with certain laboratory criteria.
Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group

This was described in the Methods section under the sub-section "Prospective
Cohort" and "Active Surveillance." Laboratory definitions were described in the Methods section under the sub-section "Laboratory Assays."

Bias 9
Describe any efforts to address potential sources of bias

This was described in the Methods section under the sub-section "Prospective
Cohort" and "Active Surveillance." A roughly equal number of subjects were targeted for recruitment from each age group. Only one subject was recruited from each household.

Study size 10
Explain how the study size was arrived at Since this was an exploratory study, the target size of the cohort was largely based on logistical considerations.

Quantitative variables 11
Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why Age groups for enrolment were determined prior to study initiation based on commonly used age categories. Since this was an exploratory study, the age groupings were arbitrary. (c) Explain how missing data were addressed Any relevant missing data were listed in the paper. These were minimal and were not included in any analyses.

(d) If applicable, explain how loss to follow-up was addressed
Subjects who completed all protocol activities were designated as "per-protocol"

subjects. Most of the analyses such as determination of subclinical infection rates and calculation of force of infection were only able to be performed on "per
protocol" subjects who completed all study activities.

(e) Describe any sensitivity analyses
Not performed.  Table 1.

Participants
(b) Indicate number of participants with missing data for each variable of interest There was no relevant missing data. Most of the basic analyses could only be done on "per-protocol" subjects who completed all study activities.
(c) Summarise follow-up time (eg, average and total amount) This is summarized throughout the paper as person-years of surveillance. In addition, much of the analyses could only be performed on "per-protocol" subjects.
Outcome data 15* Report numbers of outcome events or summary measures over time This is reported in the Results section.
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included This is provided in the Results section.

Generalisability 21 Discuss the generalisability (external validity) of the study results
This is mentioned in the Discussion section.

Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based The funding sources were mentioned.
*Give information separately for exposed and unexposed groups.