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Diarrhea remains a leading cause of death in children in developing countries, including Nicaragua, but little is known about patterns of diarrhea occurrence in Central America over long periods of time. The purpose of this study was to determine the incidence, risk factors, long-term trends, and seasonality of diarrhea in children age 2 to 14 years in Managua, Nicaragua. From 2011 to 2019, we examined episodes of diarrhea among 6,485 children who participated in a prospective cohort study and presented for care in a primary care facility. We performed a longitudinal analysis considering time-varying variables and the intra-subject correlation of outcomes. In addition, we analyzed the weekly incidence of diarrhea, applying seasonal trend decomposition to extract secular and seasonal patterns. The overall incidence rate of diarrhea was 133.4 episodes per 1,000 person-years (95% CI, 128.3-138.7). We observed a slight increase in the incidence of diarrhea from 2011 to 2019. Younger age was the strongest predictor of the risk of diarrhea, and incidence increased with every additional hour without running water in the household per day. Diarrhea incidence in Managua was seasonal, with high peaks each year between May and July. Despite reductions in childhood mortality since 1990 in Nicaragua, diarrheal morbidity remains a major problem in Managua.

Background Obesity is on the rise globally in adults and children, including in tropical areas where diseases such as dengue have a substantial burden, particularly in children. Obesity impacts risk of severe dengue disease; however, the impact on dengue virus (DENV) infection and dengue cases remains an open question. Methods We used 9 years of data from 5940 children in the Pediatric Dengue Cohort Study in Nicaragua to determine whether pediatric obesity is associated with increased susceptibility to DENV infection and symptomatic presentation. Analysis was performed using generalized estimating equations adjusted for age, sex, and preinfection DENV antibody titers. Results From 2011 to 2019, children contributed 26 273 person-years of observation, and we observed an increase in prevalence of overweight (from 12% to 17%) and obesity (from 7% to 13%). There were 1682 DENV infections and 476 dengue cases in the study population. Compared with participants with normal weight, participants with obesity had higher odds of DENV infection (adjusted odds ratio [aOR], 1.21; 95% confidence interval [CI]: 1.03–1.42) and higher odds of dengue in DENV-infected individuals (aOR, 1.59; 95% CI: 1.15–2.19). Children with obesity infected with DENV showed increased odds of presenting fever (aOR, 1.46; 95% CI: 1.05–2.02), headache (aOR, 1.51; 95% CI: 1.07–2.14), and rash (aOR, 2.26; 95% CI: 1.49–3.44) when compared with children with normal weight. Conclusions Our results indicate that obesity is associated with increased susceptibility to DENV infection and dengue cases in children, independent of age, sex, and preinfection DENV antibody titers. [ABSTRACT FROM AUTHOR]

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.

Zika virus (ZIKV) is a mosquito-borne flavivirus that is responsible for recent explosive epidemics in the Americas. Notably, ZIKV infection during pregnancy has been found to cause congenital birth defects, including microcephaly, and ZIKV has been associated with Guillain-Barré syndrome in adults. Diagnosis and surveillance of Zika in the Americas have been challenging due to similar clinical manifestations and extensive antibody cross-reactivity with endemic flaviviral diseases, such as dengue. We evaluated four serological and two reverse transcription-PCR (RT-PCR) methods in acute-phase (mean day, 1.8), early-convalescent-phase (mean day, 16.7), and late-convalescent-phase (mean, ~7 months) samples from the same individuals in a long-term pediatric cohort study in Nicaragua. Well-characterized samples from 301 cases of Zika, dengue, or non-Zika, nondengue febrile illnesses were tested. Compared to a composite reference, an in-house IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) and the NIAID-Biodefense and Emerging Infections (BEI) MAC-ELISA measuring IgM yielded sensitivities of 94.5% and 70.1% and specificities of 85.6% and 82.8%, respectively. The NS1 blockade-of-binding ELISA measuring anti-ZIKV NS1 antibody levels yielded sensitivities of 85.0% and 96.5% and specificities of 91.4% and 92.6% at early and late convalescence, respectively. An inhibition ELISA detecting total anti-ZIKV antibodies had sensitivity and specificity values of 68.3% and 58.3% for diagnosis and 94.0% and 98.6% for measuring annual infection incidence. Finally, the ZCD and Trioplex real-time RT-PCR assays detecting Zika, chikungunya, and dengue viruses both yielded a sensitivity of 96.1% and specificity of 100%. Together, these assays resolve the urgent need for diagnostic and surveillance tools for countries affected by Zika virus infections.

Zika virus (ZIKV) infection recently caused major epidemics in the Americas and is linked to congenital birth defects and Guillain-Barré Syndrome. A pilot study of ZIKV infection in Nicaraguan households was conducted from August 31 to October 21, 2016, in Managua, Nicaragua. We enrolled 33 laboratory-confirmed Zika index cases and their household members (109 contacts) and followed them on days 3-4, 6-7, 9-10, and 21, collecting serum/plasma, urine, and saliva specimens along with clinical, demographic, and socio-economic status information. Collected samples were processed by rRT-PCR to determine viral load (VL) and duration of detectable ZIKV RNA in human bodily fluids. At enrollment, 11 (10%) contacts were ZIKV rRT-PCR-positive and 23 (21%) were positive by IgM antibodies; 3 incident cases were detected during the study period. Twenty of 33 (61%) index households had contacts with ZIKV infection, with an average of 1.9 (range 1-6) positive contacts per household, and in 60% of these households, ≥50% of the members were positive for ZIKV infection. Analysis of clinical information allowed us to estimate the symptomatic to asymptomatic (S:A) ratio of 14:23 (1:1.6) among the contacts, finding 62% of the infections to be asymptomatic. The maximum number of days during which ZIKV RNA was detected was 7 days post-symptom onset in saliva and serum/plasma and 22 days in urine. Overall, VL levels in serum/plasma, saliva, and urine specimens were comparable, with means of 5.6, 5.3 and 4.5 log10 copies/ml respectively, with serum attaining the highest VL peak at 8.1 log10 copies/ml. Detecting ZIKV RNA in saliva over a similar time-period and level as in serum/plasma indicates that saliva could potentially serve as a more accessible diagnostic sample. Finding the majority of infections to be asymptomatic emphasizes the importance of silent ZIKV transmission and helps inform public health interventions in the region and globally.

Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged recently as a global health threat, causing a pandemic in the Americas. ZIKV infection mostly causes mild disease, but is linked to devastating congenital birth defects and Guillain-Barré syndrome in adults. The high level of cross-reactivity among flaviviruses and their cocirculation has complicated serological approaches to differentially detect ZIKV and dengue virus (DENV) infections, accentuating the urgent need for a specific and sensitive serological test. We previously generated a ZIKV nonstructural protein 1 (NS1)-specific human monoclonal antibody, which we used to develop an NS1-based competition ELISA. Well-characterized samples from RT-PCR-confirmed patients with Zika and individuals exposed to other flavivirus infections or vaccination were used in a comprehensive analysis to determine the sensitivity and specificity of the NS1 blockade-of-binding (BOB) assay, which was established in laboratories in five countries (Nicaragua, Brazil, Italy, United Kingdom, and Switzerland). Of 158 sera/plasma from RT-PCR-confirmed ZIKV infections, 145 (91.8%) yielded greater than 50% inhibition. Of 171 patients with primary or secondary DENV infections, 152 (88.9%) scored negative. When the control group was extended to patients infected by other flaviviruses, other viruses, or healthy donors (n = 540), the specificity was 95.9%. We also analyzed longitudinal samples from DENV-immune and DENV-naive ZIKV infections and found inhibition was achieved within 10 d postonset of illness and maintained over time. Thus, the Zika NS1 BOB assay is sensitive, specific, robust, simple, low-cost, and accessible, and can detect recent and past ZIKV infections for surveillance, seroprevalence studies, and intervention trials.

Background: Dengue is the most prevalent mosquito-borne viral disease and a major public health problem worldwide. Most primary infections with the four dengue virus serotypes (DENV1-4) are inapparent; nonetheless, whether the distribution of symptomatic versus inapparent infections by serotype varies remains unknown. Here, we present (1) the evaluation of a DENV1-4 envelope domain III multiplex microsphere-based assay (EDIII-MMBA) to serotype inapparent primary infections and (2) its application leveraging 17 years of prospective sample collection from the Nicaraguan Pediatric Dengue Cohort Study (PDCS)., Methods: We analysed primary DENV infections in the PDCS from 2004 to 2022 detected by inhibition ELISA (iELISA) or RT-PCR. First, we evaluated the performance of the EDIII-MMBA for serotyping with samples characterised by RT-PCR or focus reduction neutralisation test. Next, we analysed a subset of inapparent primary DENV infections in the PDCS with the EDIII-MMBA to evaluate the epidemiology of inapparent infections. Remaining infections were inferred using stochastic imputation, taking year and neighbourhood into account. Infection incidence and percentage of inapparent, symptomatic, and severe infections were analysed by serotype., Findings: Between Aug 30, 2004, and March 10, 2022, a total of 5931 DENV-naive participants were followed in the PDCS. There were 1626 primary infections (382 symptomatic, 1244 inapparent) detected by iELISA or RT-PCR over the study period. The EDIII-MMBA demonstrated excellent overall accuracy (100%, 95% CI 95·8-100) for serotyping inapparent primary DENV infections when evaluated against gold-standard serotyping methods. Of the 1244 inapparent infections, we analysed 574 (46%) using the EDIII-MMBA. We found that the majority of primary infections were inapparent, with DENV3 exhibiting the highest likelihood of symptomatic (pooled odds ratio compared with DENV1: 2·13, 95% CI 1·28-3·56) and severe (6·75, 2·01-22·62) primary infections, whereas DENV2 was similar to DENV1 in both analyses. Considerable within-year and between-year variation in serotype distribution between symptomatic and inapparent infections and circulation of serotypes undetected in symptomatic cases were observed in multiple years., Interpretation: Our study indicates that case surveillance skews the perceived epidemiological footprint of DENV. We reveal a more complex and intricate pattern of serotype distribution in inapparent infections. The substantial differences in infection outcomes by serotype emphasises the need for vaccines with balanced immunogenicity and efficacy across serotypes., Funding: National Institute of Allergy and Infectious Diseases (National Institutes of Health) and Bill & Melinda Gates Foundation., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AG has received institutional payments from Flu Lab and Open Philanthropy, personal honoraria from Hope College and La Jolla Institute of Immunology, payments for expert testimony from Berman and Simmons, and travel support from the Gates Foundation and National Institutes of Health (NIH), and has an advisory role with Janssen Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: ZIKV has neuroinvasive properties, and in utero exposure can cause birth defects, but little is known about the neurological and neurocognitive impacts of acquired ZIKV infection, particularly in children., Methods: We assessed neurological symptoms frequency among ZIKV-infected children within one year after ZIKV infection. Three to 5 years post-infection, these children and a matched group of uninfected children were assessed via questionnaires, neurological exams, and neuropsychological testing to evaluate the association between prior ZIKV infection and subsequent neurological symptoms, and cognitive-behavioral function., Results: Among 194 ZIKV-infected children, 3 reported asthenia, 4 reported neck pain, and 10 reported back pain within one year post-infection. At follow-up, clinician-observed cranial nerve abnormalities were significantly more common among ZIKV-infected vs. uninfected children (16 vs. 3; p < 0.01), with vestibulocochlear nerve abnormalities observed most frequently. While ZIKV-infected children scored better than uninfected on cognitive measures, this difference was not clinically meaningful., Conclusions: Neurological signs, including paresthesia and cranial nerve abnormalities, were observed among ZIKV-infected participants in our study. However, we did not observe a meaningful link between acquired ZIKV infection and subsequent neurological, cognitive, or behavioral outcomes in a representative sample. An exception may be hearing impairment and loss, which should be explored further in future studies., Impact: Neurological symptoms, though rare, were observed and reported more frequently among ZIKV-infected vs. uninfected children. These included: asthenia, neck pain, back pain, paresthesia, and cranial nerve abnormalities. Neurocognitive and behavioral test scores were similar among ZIKV-infected and uninfected children. Our study suggests that ZIKV-infected children should be monitored for neurological symptoms and cranial neuropathy to better understand the full burden of acquired ZIKV infection among children., (© 2024. The Author(s).)