Seroprevalence, risk factor, and spatial analyses of Zika virus infection after the 2016 epidemic in Managua, Nicaragua.

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 (n = 3,740) and household (n = 2,147) cohort studies, including an adult-only subset from the household cohort (n = 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.

The Nicaraguan pediatric influenza cohort study: design, methods, use of technology, and compliance.

BACKGROUND: Influenza causes substantial morbidity and mortality worldwide, yet few data exist on influenza infection rates in tropical, developing countries. In 2011, we established the Nicaraguan Pediatric Influenza Cohort Study (NPICS) to study the burden and seasonality of influenza in Nicaraguan children. Here we describe the study design, methods, and participation data of the NPICS for 2011-2013. METHODS/DESIGN: A total of 1532 children aged 0 to 12 years were enrolled into the study in 2011, and an additional 401 children were enrolled between 2012 and 2013. Children were provided with all of their medical care through the study, and data on medical visits were recorded systematically. A number of surveys were conducted together with a blood sample annually, including a height and weight measurement, a socio-economic status and risk factor survey, and a breastfeeding survey. DISCUSSION: Unique features of our study include the customized low-cost, open-source informatics system as well as the development of methods to leverage infrastructure and resources by conducting multiple studies in the same setting while maximizing protocol adherence and quality control. These methods should be useful to others conducting large cohort studies, particularly in low-resource settings.

The Nicaraguan pediatric dengue cohort study: incidence of inapparent and symptomatic dengue virus infections, 2004-2010.

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.

Evaluation of the diagnostic utility of the traditional and revised WHO dengue case definitions.

Dengue, a mosquito-borne viral illness, is a major public health problem worldwide, and its incidence continues to increase. In 2009, the World Health Organization published guidelines that included a revision of the dengue case definition. Compared to the traditional definition, the revised case definition relies more on signs than on symptoms, making it more applicable to young children. We evaluated the diagnostic utility of both case definitions in two studies of pediatric dengue in Managua, Nicaragua. In a community-based cohort study, we included data from 3,407 suspected dengue cases, of which 476 were laboratory-confirmed. In the second study, we collected information from 1,160 participants recruited at the national pediatric reference hospital (723 laboratory-confirmed). In the cohort study, the traditional definition had 89.3% sensitivity and 43.1% specificity, while the revised definition yielded similar sensitivity (86.6%) and higher specificity (55.2%, p<0.001). In the hospital study, the traditional case definition yielded 96.7% sensitivity and 22.0% specificity, whereas the revised case definition had higher sensitivity (99.3%, p<0.001) but lower specificity (8.5%, p<0.001). We then evaluated the performance of two diagnostic models based on the signs/symptoms included in each definition by analyzing the effect of increasing numbers of signs/symptoms on the sensitivity and specificity of case capture. Receiver operating characteristic analysis showed a slightly better performance for the revised model in both studies. Interestingly, despite containing less symptoms that cannot be readily expressed by children aged less than 4 years, the revised definition did not perform better in this age group. Overall, our results indicate that both case definitions have similar capacity to diagnose dengue. Owing to their high sensitivity and low specificity, they should be primarily used for screening purposes. However, in a primary care setting, neither of the case definitions performed well as a screening test in younger children.

Index cluster study of dengue virus infection in Nicaragua.

Traditional study designs do not identify acute asymptomatic or pre-symptomatic dengue virus (DENV) infections, thus limiting our understanding of immunologic and viral factors that modulate infection outcome. In the 2006 and 2007 dengue seasons, we conducted a pilot index cluster study in Managua, Nicaragua, in which 442 persons living within 50 meters of 22 index cases identified through an ongoing pediatric cohort study were evaluated for DENV infection. Post-enrollment and pre-enrollment DENV infections were confirmed in 12 (2.7%) and 19 (4.3%) contacts, respectively. Five (42%) post-enrollment infections were asymptomatic, and DENV-2 was identified in 9 (75%) infections. Phylogenetic analysis with full-length DENV genomic sequence from contacts, index cases, and cohort dengue cases indicated focal transmission and infection outside the local area. We demonstrate the feasibility of identification of acute asymptomatic and pre-symptomatic cases in urban Latin America, the first report of such a study in the Americas, and identify age and concomitant immunity to DENV of contacts as a key factor in index cluster study design.

High dengue case capture rate in four years of a cohort study in Nicaragua compared to national surveillance data.

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.

Trends in patterns of dengue transmission over 4 years in a pediatric cohort study in Nicaragua.

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 approximately 3800 children initially aged 2-9 years 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 from 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.

The Nicaraguan pediatric dengue cohort study: study design, methods, use of information technology, and extension to other infectious diseases.

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.

Quantitative assessment of the benefits of specific information technologies applied to clinical studies in developing countries.

Clinical studies and trials require accessibility of large amounts of high-quality information in a timely manner, often daily. The integrated application of information technologies can greatly improve quality control as well as facilitate compliance with established standards such as Good Clinical Practice (GCP) and Good Laboratory Practice (GLP). We have customized and implemented a number of information technologies, such as personal data assistants (PDAs), geographic information system (GIS), and barcode and fingerprint scanning, to streamline a pediatric dengue cohort study in Managua, Nicaragua. Quantitative data was obtained to assess the actual contribution of each technology in relation to processing time, accuracy, real-time access to data, savings in consumable materials, and time to proficiency in training sessions. In addition to specific advantages, these information technologies benefited not only the study itself but numerous routine clinical and laboratory processes in the health center and laboratories of the Nicaraguan Ministry of Health.