Background Dengue is the most prevalent mosquito-borne viral disease in humans and a major urban public health problem worldwide. Methods A prospective cohort study of ~3,800 children initially aged 2-9 years old was established in Managua, Nicaragua, in 2004 to study the natural history of dengue transmission in an urban pediatric population. Blood samples from healthy subjects were collected annually prior to the dengue season, and identification of dengue cases occurred via enhanced passive surveillance at the study health center. Results Over the first four years of the study, seroprevalence of anti-dengue virus (DENV) antibodies increased from 22-40% in the 2-year-old cohort and 90-95% in the 9-year-old cohort. The incidence of symptomatic dengue cases and the ratio of inapparent to symptomatic DENV infection varied substantially year-to-year. The switch in dominant transmission from DENV-1 to DENV-2 was accompanied by an increase in disease severity but, paradoxically, a decrease in transmission. Phylogeographic analysis of full-length DENV-2 sequences revealed strong geographic clustering of dengue cases. Conclusions This large-scale cohort study of dengue in the Americas demonstrates year-to-year variation of dengue within a pediatric population, revealing expected patterns in transmission while highlighting the impact of interventions, climate, and viral evolution.

Dengue is a mosquito-borne viral disease that is a major public health problem worldwide. In 2004, the Pediatric Dengue Cohort Study was established in Managua, Nicaragua, to study the natural history and transmission of dengue in children. Here, the authors describe the study design, methods, and results from 2004 to 2008. Initially, 3,721 children 2–9 years of age were recruited through door-to-door visits. Each year, new children aged 2 years are enrolled in the study to maintain the age structure. Children are provided with medical care through the study, and data from each medical visit are recorded on systematic study forms. All participants presenting with suspected dengue or undifferentiated fever are tested for dengue by virologic, serologic, and molecular biologic assays. Yearly blood samples are collected to detect inapparent dengue virus infections. Numerous information and communications technologies are used to manage study data, track samples, and maintain quality control, including personal data assistants, barcodes, global information systems, and fingerprint scans. Close collaboration with the Nicaraguan Ministry of Health and use of almost entirely local staff are essential components for success. This study is providing critical data on the epidemiology and transmission of dengue in the Americas needed for future vaccine trials.

Dengue, caused by the four serotypes of dengue virus (DENV), is the most prevalent mosquito-borne viral disease of humans. To examine the incidence and transmission of dengue, the authors performed a prospective community-based cohort study in 5,545 children aged 2–14 years in Managua, Nicaragua, between 2004 and 2010. Children were provided with medical care through study physicians who systematically recorded medical consult data, and yearly blood samples were collected to evaluate DENV infection incidence. The incidence of dengue cases observed was 16.1 cases (range 3.4–43.5) per 1,000 person-years (95% CI: 14.5, 17.8), and a pattern of high dengue case incidence every other year was observed. The incidence of DENV infections was 90.2 infections (range 45.2–105.3) per 1,000 person-years (95% CI: 86.1, 94.5). The majority of DENV infections in young children (<6 years old) were primary (60%) and the majority of infections in older children (≥9 years of age) were secondary (82%), as expected. The incidence rate of second DENV infections (121.3 per 1,000 person-years; 95% CI: 102.7, 143.4) was significantly higher than the incidence rate of primary DENV infections (78.8 per 1,000 person-years; 95% CI: 73.2, 84.9). The rigorous analytic methodology used in this study, including incidence reporting in person-years, allows comparison across studies and across different infectious diseases. This study provides important information for understanding dengue epidemiology and informing dengue vaccine policy.

In 2015, a Zika epidemic in Brazil began spreading throughout the Americas. Zika virus (ZIKV) entered Managua, Nicaragua, in January 2016 and caused an epidemic that peaked in July-September 2016. ZIKV seropositivity was estimated among participants of pediatric ( = 3,740) and household ( = 2,147) cohort studies, including an adult-only subset from the household cohort ( = 1,074), in Managua. Seropositivity was based on a highly sensitive and specific assay, the Zika NS1 blockade-of-binding ELISA, which can be used in dengue-endemic populations. Overall seropositivity for the pediatric (ages 2-14), household (ages 2-80), and adult (ages 15-80) cohorts was 36, 46, and 56%, respectively. Trend, risk factor, and contour mapping analyses demonstrated that ZIKV seroprevalence increased nonlinearly with age and that body surface area was statistically associated with increasing seroprevalence in children. ZIKV seropositivity was higher in females than in males across almost all ages, with adjusted prevalence ratios in children and adults of 1.11 (95% CI: 1.02-1.21) and 1.14 (95% CI: 1.01-1.28), respectively. No household-level risk factors were statistically significant in multivariate analyses. A spatial analysis revealed a 10-15% difference in the risk of ZIKV infections across our 3-km-wide study site, suggesting that ZIKV infection risk varies at small spatial scales. To our knowledge, this is the largest ZIKV seroprevalence study reported in the Americas, and the only one in Central America and in children to date. It reveals a high level of immunity against ZIKV in Managua as a result of the 2016 epidemic, making a second large Zika epidemic unlikely in the near future.

Dengue is a major public health problem in tropical and subtropical regions; however, under-reporting of cases to national surveillance systems hinders accurate knowledge of disease burden and costs. Laboratory-confirmed dengue cases identified through the Nicaraguan Pediatric Dengue Cohort Study (PDCS) were compared to those reported from other health facilities in Managua to the National Epidemiologic Surveillance (NES) program of the Nicaraguan Ministry of Health. Compared to reporting among similar pediatric populations in Managua, the PDCS identified 14 to 28 (average 21.3) times more dengue cases each year per 100,000 persons than were reported to the NES. Applying these annual expansion factors to national-level data, we estimate that the incidence of confirmed pediatric dengue throughout Nicaragua ranged from 300 to 1000 cases per 100,000 persons. We have estimated a much higher incidence of dengue than reported by the Ministry of Health. A country-specific expansion factor for dengue that allows for a more accurate estimate of incidence may aid governments and other institutions calculating disease burden, costs, resource needs for prevention and treatment, and the economic benefits of drug and vaccine development.