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Papers by Filemon Bucardo

Research paper thumbnail of Visual findings in children exposed to Zika in utero in Nicaragua

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2023

Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in childre... more Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in children exposed to Zika virus (ZIKV) in utero but born without congenital Zika syndrome (CZS) is limited. We hypothesized that children exposed to ZIKV in utero born without CZS may have visual impairments in early childhood. We performed ophthalmic examination between 16 and 21 months of age and neurodevelopment assessment at 24 months of age with the Mullen Scales of Early Learning test (MSEL) on children enrolled in a cohort born to women pregnant during and shortly after the ZIKV epidemic in Nicaragua (2016-2017). ZIKV exposure status was defined based on maternal and infant serological testing. Visual impairment was defined as abnormal if the child had an abnormal ophthalmic exam and/or low visual reception score in the MSEL assessment. Of 124 children included in the analysis, 24 (19.4%) were classified as ZIKV-exposed and 100 (80.6%) unexposed according to maternal or cord blood serology. Ophthalmic examination showed that visual acuity did not differ significantly between groups, thus, 17.4% of ZIKV-exposed and 5.2% of unexposed had abnormal visual function (p = 0.07) and 12.5% of the ZIKV-exposed and 2% of the unexposed had abnormal contrast testing (p = 0.05). Low MSEL visual reception score was 3.2fold higher in ZIKV-exposed than unexposed children, but not statistically significant (OR 3.2, CI: 0.8-14.0; p = 0.10). Visual impairment (a composite measure of visual function or low MESL visual reception score) was present in more ZIKV-exposed than in unexposed children (OR 3.7, CI: 1.2, 11.0; p = 0.02). However, the limited sample size warrants future PLOS NEGLECTED TROPICAL DISEASES

Research paper thumbnail of Serologic surveillance of maternal Zika infection in a prospective cohort in Leon, Nicaragua during the peak of the Zika epidemic

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2020

Background Zika virus caused thousands of congenital anomalies during a recent epidemic. Because ... more Background Zika virus caused thousands of congenital anomalies during a recent epidemic. Because Zika emerged in areas endemic for dengue and these related flaviviruses elicit cross-reactive antibodies, it is challenging to serologically monitor pregnant women for Zika infection. Methods A prospective cohort of 253 pregnant women was established in Leó n, Nicaragua. Women were followed during prenatal care through delivery. Serologic specimens were obtained at each visit, and birth outcome was recorded. Established flavivirus serologic methods were adapted to determine Zika seroprevalence, and a stepwise testing algorithm estimated timing of Zika infection in relation to pregnancy. Results Zika seroprevalence was approximately 59% among women tested. Neutralization testing was highly concordant with Zika NS1 BOB results. Per study algorithm, 21% (40/187) of women were classified as experiencing Incident ZIKV infection during pregnancy.

Research paper thumbnail of The Association Between Fecal Biomarkers of Environmental Enteropathy and Rotavirus Vaccine Response in Nicaraguan Infants

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2017

Vaccine Reports Background: Environmental enteropathy (EE) is a common intestinal condition among... more Vaccine Reports Background: Environmental enteropathy (EE) is a common intestinal condition among children living in low-and middle-income countries and is associated with diminished enteric immunity to gastrointestinal pathogens, and possibly to oral vaccine antigens. The goal of this study was to examine associations between biomarkers of EE and immunogenicity to the pentavalent rotavirus vaccine (RV5). Methods: Infants were recruited 1 day before their first RV5 immunization in León, Nicaragua, from public health rosters. Infants provided a preimmunization blood and stool sample, and a second blood sample 1 month after receipt of RV5. We measured immunoglobin A (IgA) seroconversion to the first dose of RV5 and concentrations of 4 previously identified fecal biomarkers of EE (alpha-1 antitrypsin, neopterin, myeloperoxidase and calprotectin). We then assessed associations between concentrations of these biomarkers, both individually and as combined scores, and seroconversion to the first dose of RV5. Results: Of the 43 enrolled infants, 24 (56%) seroconverted after the first dose of RV5. As compared with infants who seroconverted, those who did not seroconvert had higher median concentrations of both myeloperoxidase (3.1 vs. 1.1 µg/mL, P = 0.002) and calprotectin (199.1 vs. 156.2 µg/mL, P = 0.03). Further, those who did not seroconvert had a higher median combined score of the 4 biomarkers as compared with those who seroconverted (6.5 vs. 4.5, P = 0.017). Conclusions: We found an association between biomarkers of EE and seroconversion to the first dose of RV5. It is possible that interventions that prevent or ameliorate EE may also improve oral rotavirus vaccine response.

Research paper thumbnail of Visual findings in children exposed to Zika in utero in Nicaragua

PLOS Neglected Tropical Diseases, May 19, 2023

Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in childre... more Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in children exposed to Zika virus (ZIKV) in utero but born without congenital Zika syndrome (CZS) is limited. We hypothesized that children exposed to ZIKV in utero born without CZS may have visual impairments in early childhood. We performed ophthalmic examination between 16 and 21 months of age and neurodevelopment assessment at 24 months of age with the Mullen Scales of Early Learning test (MSEL) on children enrolled in a cohort born to women pregnant during and shortly after the ZIKV epidemic in Nicaragua (2016-2017). ZIKV exposure status was defined based on maternal and infant serological testing. Visual impairment was defined as abnormal if the child had an abnormal ophthalmic exam and/or low visual reception score in the MSEL assessment. Of 124 children included in the analysis, 24 (19.4%) were classified as ZIKV-exposed and 100 (80.6%) unexposed according to maternal or cord blood serology. Ophthalmic examination showed that visual acuity did not differ significantly between groups, thus, 17.4% of ZIKV-exposed and 5.2% of unexposed had abnormal visual function (p = 0.07) and 12.5% of the ZIKV-exposed and 2% of the unexposed had abnormal contrast testing (p = 0.05). Low MSEL visual reception score was 3.2fold higher in ZIKV-exposed than unexposed children, but not statistically significant (OR 3.2, CI: 0.8-14.0; p = 0.10). Visual impairment (a composite measure of visual function or low MESL visual reception score) was present in more ZIKV-exposed than in unexposed children (OR 3.7, CI: 1.2, 11.0; p = 0.02). However, the limited sample size warrants future PLOS NEGLECTED TROPICAL DISEASES

Research paper thumbnail of Antibody Immunity to Zika Virus among Young Children in a Flavivirus-Endemic Area in Nicaragua

Viruses, Mar 21, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Rotavirus Prevalence in the Primary Care Setting in Nicaragua after Universal Infant Rotavirus Immunization

American Journal of Tropical Medicine and Hygiene, Nov 1, 2011

Research paper thumbnail of Association of Genetic Polymorphisms in DC-SIGN, Toll-Like Receptor 3, and Tumor Necrosis Factor α Genes and the Lewis-Negative Phenotype With Chikungunya Infection and Disease in Nicaragua

The Journal of Infectious Diseases, Jun 27, 2020

Background. Chikungunya infections range from subclinical infection to debilitating arthralgia an... more Background. Chikungunya infections range from subclinical infection to debilitating arthralgia and to chronic inflammatory rheumatism. Tumor necrosis factor (TNF) α, DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin), Tolllike receptor (TLR) 3, and blood groups have been directly or indirectly implicated in the susceptibility and pathogenesis of chikungunya. Methods. To test the hypothesis that polymorphisms in genes coding for these molecules determine clinical outcomes of chikungunya infection, a retrospective case-control study was performed in León, Nicaragua. The study included 132 case patients and 132 controls, matched for age, sex and neighborhood. Case patients had clinical symptoms of chikungunya, which was diagnosed by means of polymerase chain reaction. Controls were individuals not reporting abrupt presentation of clinical chikungunya-like symptoms. Polymorphisms were identified by TaqMan single-nucleotide polymorphism genotyping assays. Results. After adjustment for sociodemographic risk factors, chikungunya disease was associated with polymorphism in DC-SIGN and TLR3 genes (odds ratios, 5.2 and 3.3, respectively), and TNF-α with reduced persistent joint pain (0.24). Persistent joint pain was also associated with age, female sex and other comorbid conditions. Most interestingly, the Lewis-negative phenotype was strongly associated with both symptomatic chikungunya and immunoglobulin G seropositivity (odds ratios, 2.7, and 3.3, respectively). Conclusion. This study identified polymorphisms in DC-SIGN, TLR3, and TNF-α genes as well as Lewis-negative phenotype as risk factors for chikungunya infection and disease progression.

Research paper thumbnail of Impact of vaccination on the molecular epidemiology and evolution of group A rotaviruses in Latin America and factors affecting vaccine efficacy

Infection, Genetics and Evolution, Aug 1, 2015

hospitalization, RV is still contributing to the burden of diarrhea that persists in hospital set... more hospitalization, RV is still contributing to the burden of diarrhea that persists in hospital settings in sev-33 eral Latin American countries, where RV vaccination is being implemented. Due to the extensive genomic 34 and antigenic diversity, among co-circulating human RV, a major concern has been that the introduction 35 of RV vaccination could exert selection pressure leading to higher prevalence of strains not included in 36 the vaccines and/or emergence of new strains, thus, reducing the efficacy of vaccination. Here we review 37 the molecular epidemiology of RV in Latin America and explore issues of RV evolution and selection in 38 light of vaccination. We further explore etiologies behind the large burden of diarrhea remaining after 39 vaccination in some countries and discuss plausible reasons for vaccine failures.

Research paper thumbnail of Sapovirus: an important cause of acute gastroenteritis in children

The Lancet Child & Adolescent Health, Nov 1, 2019

Sapovirus infections are responsible for both sporadic cases and occasional outbreaks of acute ga... more Sapovirus infections are responsible for both sporadic cases and occasional outbreaks of acute gastroenteritis. While all age groups are affected, children younger than five years of age have the highest burden of disease. Sharing many similarities with closely-related noroviruses, common symptoms of sapovirus gastroenteritis include vomiting and diarrhea, which typically resolve within one week. 1 Sapovirus has also been detected in asymptomatic individuals. 1,2 In recent years, there has been a growing awareness of the importance of sapoviruses to the health of children, due in part to the increasing use of molecular-based diagnostics. Using these diagnostics, sapovirus was detected in 3% to 17% of children with gastroenteritis in high and low-income countries. 2-4 Following rotavirus vaccine introduction in Nicaragua, sapovirus was second only to norovirus as the most commonly detected enteropathogen among children under age five years with gastroenteritis. 5 In this setting, sapovirus was also identified in 15% of children hospitalized for gastroenteritis. 6 Children with sapovirus gastroenteritis are often co-infected with multiple enteric pathogens, especially in low-and middle-income countries (LMIC), which makes it a challenge to understand the true burden of disease. The Malnutrition and Enteric Disease (MAL-ED) study, a multi-site prospective birth cohort study of enteric infections in children in LMIC, used a nested case-control design to estimate pathogen-specific attributable disease burdens. Using this approach, they found sapovirus to have the third highest attributable incidence for

Research paper thumbnail of Vaccine-derived NSP2 segment in rotaviruses from vaccinated children with gastroenteritis in Nicaragua

Infection, Genetics and Evolution, Aug 1, 2012

Rotavirus (RV) vaccination programs have been established in several countries using the humanatt... more Rotavirus (RV) vaccination programs have been established in several countries using the humanattenuated G1P[8] monovalent vaccine Rotarix ™ (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] pentavalent vaccine RotaTeq ™ (Merck). The efficacy of both vaccines is high (~90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007-2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11 G1P[8], 1 G3P[8]) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1P[8] viruses and the single G3P[8] virus had genome constellations typical of human G1P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P[8] RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggests that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs.

Research paper thumbnail of Understanding Asymptomatic Norovirus Infections

EClinicalMedicine, Aug 1, 2018

Research paper thumbnail of The seroprevalence of<i>Taenia solium</i>cysticercosis among epileptic patients in León, Nicaragua, as evaluated by ELISA and western blotting

Annals of Tropical Medicine and Parasitology, 2005

Abstract: The Taenia solium taeniasis/cysticercosis complex is an important public-health problem... more Abstract: The Taenia solium taeniasis/cysticercosis complex is an important public-health problem in several countries, where many epileptic seizures appear to be associated with neurocysticercosis. As few data on this problem in Nicaragua exist, the seroprevalence of ...

Research paper thumbnail of Immune Imprinting Drives Human Norovirus Potential for Global Spread

mBio

In our model, preepidemic human norovirus variants harbor genetic diversification that translates... more In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree.

Research paper thumbnail of Household Surveillance for Norovirus Gastroenteritis in a Nicaraguan Birth Cohort: A Nested Case—Control Analysis of Norovirus Risk Factors

Pathogens, Mar 22, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Large increase of rotavirus diarrhoea in the hospital setting associated with emergence of G12 genotype in a highly vaccinated population in Nicaragua

Clinical Microbiology and Infection, Jun 1, 2015

Rotaviruses (RVs) are a major cause of severe diarrhoea in young children. Nicaragua introduced r... more Rotaviruses (RVs) are a major cause of severe diarrhoea in young children. Nicaragua introduced routine immunization with the pentavalent RV vaccine (RV5) in 2006, which greatly reduced the incidence of diarrhoea. A remaining concern has been the possible emergence of new RV strains to which the vaccination has less effect. In this study, 837 children with diarrhoea in hospital settings were investigated for RV between May 2011 and July 2013. RVs were subsequently typed by multiplex PCR and/or sequencing. Fecal anti-RV IgA titres for a subset of RV-infected (n = 137) and noninfected children (n = 52) were determined with an in-house enzyme-linked immunosorbent assay. The RV detection rate was 8% in 2011, followed by a sharp increase to 29% in 2012 and 19% in 2013. This was associated with emergence and predominance of genotype G12 RV, from 0% in 2011 to 66% in 2012 and 82% in 2013, infecting children from 1 month to 10 years of age. Two sequenced G12 strains showed a Wa-like genome with genotype G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1, similar to the globally emerging G12 strains. Fecal anti-RV IgA analysis showed that most G12-infected and noninfected children had been in contact with either vaccine or wild RV strains, but such antibodies did not prevent symptomatic G12 infection. A marked increase of RV was evident in the hospital setting associated with a nationwide emergence and predominance of RV G12 genotype in a population with high RV5 vaccine coverage.

Research paper thumbnail of Genetic susceptibility to symptomatic norovirus infection in Nicaragua

Journal of Medical Virology, Apr 1, 2009

Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in... more Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in populations from Europe, Asia, and USA. In this study, we have investigated if histo-blood group antigens can predict susceptibility to diarrhea caused by NoV in Nicaragua, Central America, and if this can be reflected in antibodyprevalence and titer to NoV among individuals with different histo-blood group antigen phenotypes. Investigation of 28 individuals infected with NoV and 131 population controls revealed 6% of non-secretors in the population and nil non-secretors among patients infected with NoV, suggesting that non-secretors may be protected against NoV disease in Nicaragua. Surprisingly, 25% of the population was Lewis negative (Le aÀbÀ). NoV infections with genogroup I (GI) and GII occurred irrespective of Lewis genotype, but none of the Lewis a positive (Le a þ bÀ) were infected. The globally dominating GII.4 virus infected individuals of all blood groups except AB (n ¼ 5), while the GI viruses (n ¼ 4) infected only blood type O individuals. Furthermore, O blood types were susceptible to infections with GI.4, GII.4, GII.7, GII.17, and GII.18-Nica viruses, suggesting that secretors with blood type O are susceptible (OR ¼ 1.52) and non-secretors resistant. The overall antibody-prevalence to NoV GII.3 VLP was 62% with the highest prevalence among blood type B carriers (70%) followed by A (68%) and O (62%). All four investigated individuals carrying blood type AB were antibody-negative. Among secretors, 63% were antibody-positive compared to 33% among non-secretors (P ¼ 0.151). This study extends previous knowledge about the histo-blood group antigens role in NoV disease in a population with different genetic background than North American and European.

Research paper thumbnail of Risk Factors and Clinical Profile of Sapovirus-associated Acute Gastroenteritis in Early Childhood: A Nicaraguan Birth Cohort Study

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2021

Background: Sapovirus is increasingly recognized as an important cause of acute gastroenteritis (... more Background: Sapovirus is increasingly recognized as an important cause of acute gastroenteritis (AGE) in children. We identified risk factors and characterized the clinical profile of sapovirus AGE in a birth cohort in León, Nicaragua. Methods: We conducted a case-control study nested within a birth cohort (n=444). Fieldworkers conducted weekly household AGE surveillance. AGE stools were tested for sapovirus by RT-qPCR. For each first sapovirus episode, we selected two healthy age-matched controls and estimated independent risk factors of sapovirus AGE using conditional logistic regression. We compared clinical characteristics of sapovirus AGE episodes with episodes associated with other etiologies, and identified co-infections with other enteric pathogens.

Research paper thumbnail of Clinical characteristics, risk factors, and population attributable fraction for campylobacteriosis in a nicaraguan birth cohort

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2021

Campylobacteriosis is an important contributor to the global burden of acute gastroenteritis (AGE... more Campylobacteriosis is an important contributor to the global burden of acute gastroenteritis (AGE). In Nicaragua, the burden, risk factors, and species diversity for infant campylobacteriosis are unknown. Between June 2017 and December 2018, we enrolled 444 infants from León, Nicaragua, in a population-based birth cohort, conducting weekly household AGE surveillance. First, we described clinical characteristics of symptomatic Campylobacter infections, and then compared clinical characteristics between Campylobacter jejuni/coli and non-jejuni/coli infections. Next, we conducted a nested case-control analysis to examine campylobacteriosis risk factors. Finally, we estimated the population attributable fraction of campylobacteriosis among infants experiencing AGE. Of 296 AGE episodes in the first year of life, Campylobacter was detected in 59 (20%), 39 were C. jejuni/coli, and 20 were non-jejuni/coli species, including the first report of Campylobacter vulpis infection in humans. Acute gastroenteritis symptoms associated with C. jejuni/coli lasted longer than those attributed to other Campylobacter species. In a conditional logistic regression model, chickens in the home (odds ratio [OR]: 3.8, 95% CI: 1.4-9.8), a prior AGE episode (OR: 3.3; 95% CI: 1.4-7.8), and poverty (OR: 0.4; 95% CI: 0.2-0.9) were independently associated with campylobacteriosis. Comparing 90 infants experiencing AGE with 90 healthy controls, 22.4% (95% CI: 11.2-32.1) of AGE episodes in the first year of life could be attributed to Campylobacter infection. Campylobacter infections contribute substantially to infant AGE in León, Nicaragua, with non-jejuni/ coli species frequently detected. Reducing contact with poultry in the home and interventions to prevent all-cause AGE may reduce campylobacteriosis in this setting.

Research paper thumbnail of Zika RNA and Flavivirus-Like Antigens in the Sperm Cells of Symptomatic and Asymptomatic Subjects

Viruses, Jan 21, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Risk Factors for Norovirus Gastroenteritis among Nicaraguan Children

American Journal of Tropical Medicine and Hygiene, Sep 7, 2017

Norovirus is a leading cause of pediatric gastroenteritis. Understanding norovirus epidemiology i... more Norovirus is a leading cause of pediatric gastroenteritis. Understanding norovirus epidemiology is essential for reducing disease burden. We conducted a case-control study to describe the distribution, clinical features, and risk factors of norovirus gastroenteritis among children < 5 years of age in León, Nicaragua. Cases were children testing positive for norovirus and controls were children living in the cases' communities. Study staff interviewed mothers of enrolled cases and controls to obtain detailed exposure information including food, water, and sanitation sources; recent exposures; household characteristics; and handwashing practices. In addition, study staff requested stool samples to be tested for norovirus from select household members. We used descriptive statistics to understand the epidemiologic and clinical features of gastroenteritis episodes. To analyze potential risk factors, we used Firth's penalized logistic regression to estimate crude and adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). There were 102 children with gastroenteritis, 18 cases of norovirus and 31 controls. Norovirus cases occurred later in the year, corresponding to a delay in the rainy season. Cases were more likely to have a household member with norovirus in their stool as compared with controls [crude OR: 13.3 (95% CI: 2.5, 136.2) and adjusted OR: 11.5 (95% CI: 1.6, 223.2)]. In addition, alcohol-based hand sanitizer use among household members was reported for 10 (32%) of controls and but never for cases. Further research is needed to understand household transmission of norovirus in low-and middle-income countries and the potential impact of hand sanitizer use.

Research paper thumbnail of Visual findings in children exposed to Zika in utero in Nicaragua

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2023

Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in childre... more Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in children exposed to Zika virus (ZIKV) in utero but born without congenital Zika syndrome (CZS) is limited. We hypothesized that children exposed to ZIKV in utero born without CZS may have visual impairments in early childhood. We performed ophthalmic examination between 16 and 21 months of age and neurodevelopment assessment at 24 months of age with the Mullen Scales of Early Learning test (MSEL) on children enrolled in a cohort born to women pregnant during and shortly after the ZIKV epidemic in Nicaragua (2016-2017). ZIKV exposure status was defined based on maternal and infant serological testing. Visual impairment was defined as abnormal if the child had an abnormal ophthalmic exam and/or low visual reception score in the MSEL assessment. Of 124 children included in the analysis, 24 (19.4%) were classified as ZIKV-exposed and 100 (80.6%) unexposed according to maternal or cord blood serology. Ophthalmic examination showed that visual acuity did not differ significantly between groups, thus, 17.4% of ZIKV-exposed and 5.2% of unexposed had abnormal visual function (p = 0.07) and 12.5% of the ZIKV-exposed and 2% of the unexposed had abnormal contrast testing (p = 0.05). Low MSEL visual reception score was 3.2fold higher in ZIKV-exposed than unexposed children, but not statistically significant (OR 3.2, CI: 0.8-14.0; p = 0.10). Visual impairment (a composite measure of visual function or low MESL visual reception score) was present in more ZIKV-exposed than in unexposed children (OR 3.7, CI: 1.2, 11.0; p = 0.02). However, the limited sample size warrants future PLOS NEGLECTED TROPICAL DISEASES

Research paper thumbnail of Serologic surveillance of maternal Zika infection in a prospective cohort in Leon, Nicaragua during the peak of the Zika epidemic

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2020

Background Zika virus caused thousands of congenital anomalies during a recent epidemic. Because ... more Background Zika virus caused thousands of congenital anomalies during a recent epidemic. Because Zika emerged in areas endemic for dengue and these related flaviviruses elicit cross-reactive antibodies, it is challenging to serologically monitor pregnant women for Zika infection. Methods A prospective cohort of 253 pregnant women was established in Leó n, Nicaragua. Women were followed during prenatal care through delivery. Serologic specimens were obtained at each visit, and birth outcome was recorded. Established flavivirus serologic methods were adapted to determine Zika seroprevalence, and a stepwise testing algorithm estimated timing of Zika infection in relation to pregnancy. Results Zika seroprevalence was approximately 59% among women tested. Neutralization testing was highly concordant with Zika NS1 BOB results. Per study algorithm, 21% (40/187) of women were classified as experiencing Incident ZIKV infection during pregnancy.

Research paper thumbnail of The Association Between Fecal Biomarkers of Environmental Enteropathy and Rotavirus Vaccine Response in Nicaraguan Infants

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2017

Vaccine Reports Background: Environmental enteropathy (EE) is a common intestinal condition among... more Vaccine Reports Background: Environmental enteropathy (EE) is a common intestinal condition among children living in low-and middle-income countries and is associated with diminished enteric immunity to gastrointestinal pathogens, and possibly to oral vaccine antigens. The goal of this study was to examine associations between biomarkers of EE and immunogenicity to the pentavalent rotavirus vaccine (RV5). Methods: Infants were recruited 1 day before their first RV5 immunization in León, Nicaragua, from public health rosters. Infants provided a preimmunization blood and stool sample, and a second blood sample 1 month after receipt of RV5. We measured immunoglobin A (IgA) seroconversion to the first dose of RV5 and concentrations of 4 previously identified fecal biomarkers of EE (alpha-1 antitrypsin, neopterin, myeloperoxidase and calprotectin). We then assessed associations between concentrations of these biomarkers, both individually and as combined scores, and seroconversion to the first dose of RV5. Results: Of the 43 enrolled infants, 24 (56%) seroconverted after the first dose of RV5. As compared with infants who seroconverted, those who did not seroconvert had higher median concentrations of both myeloperoxidase (3.1 vs. 1.1 µg/mL, P = 0.002) and calprotectin (199.1 vs. 156.2 µg/mL, P = 0.03). Further, those who did not seroconvert had a higher median combined score of the 4 biomarkers as compared with those who seroconverted (6.5 vs. 4.5, P = 0.017). Conclusions: We found an association between biomarkers of EE and seroconversion to the first dose of RV5. It is possible that interventions that prevent or ameliorate EE may also improve oral rotavirus vaccine response.

Research paper thumbnail of Visual findings in children exposed to Zika in utero in Nicaragua

PLOS Neglected Tropical Diseases, May 19, 2023

Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in childre... more Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in children exposed to Zika virus (ZIKV) in utero but born without congenital Zika syndrome (CZS) is limited. We hypothesized that children exposed to ZIKV in utero born without CZS may have visual impairments in early childhood. We performed ophthalmic examination between 16 and 21 months of age and neurodevelopment assessment at 24 months of age with the Mullen Scales of Early Learning test (MSEL) on children enrolled in a cohort born to women pregnant during and shortly after the ZIKV epidemic in Nicaragua (2016-2017). ZIKV exposure status was defined based on maternal and infant serological testing. Visual impairment was defined as abnormal if the child had an abnormal ophthalmic exam and/or low visual reception score in the MSEL assessment. Of 124 children included in the analysis, 24 (19.4%) were classified as ZIKV-exposed and 100 (80.6%) unexposed according to maternal or cord blood serology. Ophthalmic examination showed that visual acuity did not differ significantly between groups, thus, 17.4% of ZIKV-exposed and 5.2% of unexposed had abnormal visual function (p = 0.07) and 12.5% of the ZIKV-exposed and 2% of the unexposed had abnormal contrast testing (p = 0.05). Low MSEL visual reception score was 3.2fold higher in ZIKV-exposed than unexposed children, but not statistically significant (OR 3.2, CI: 0.8-14.0; p = 0.10). Visual impairment (a composite measure of visual function or low MESL visual reception score) was present in more ZIKV-exposed than in unexposed children (OR 3.7, CI: 1.2, 11.0; p = 0.02). However, the limited sample size warrants future PLOS NEGLECTED TROPICAL DISEASES

Research paper thumbnail of Antibody Immunity to Zika Virus among Young Children in a Flavivirus-Endemic Area in Nicaragua

Viruses, Mar 21, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Rotavirus Prevalence in the Primary Care Setting in Nicaragua after Universal Infant Rotavirus Immunization

American Journal of Tropical Medicine and Hygiene, Nov 1, 2011

Research paper thumbnail of Association of Genetic Polymorphisms in DC-SIGN, Toll-Like Receptor 3, and Tumor Necrosis Factor α Genes and the Lewis-Negative Phenotype With Chikungunya Infection and Disease in Nicaragua

The Journal of Infectious Diseases, Jun 27, 2020

Background. Chikungunya infections range from subclinical infection to debilitating arthralgia an... more Background. Chikungunya infections range from subclinical infection to debilitating arthralgia and to chronic inflammatory rheumatism. Tumor necrosis factor (TNF) α, DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin), Tolllike receptor (TLR) 3, and blood groups have been directly or indirectly implicated in the susceptibility and pathogenesis of chikungunya. Methods. To test the hypothesis that polymorphisms in genes coding for these molecules determine clinical outcomes of chikungunya infection, a retrospective case-control study was performed in León, Nicaragua. The study included 132 case patients and 132 controls, matched for age, sex and neighborhood. Case patients had clinical symptoms of chikungunya, which was diagnosed by means of polymerase chain reaction. Controls were individuals not reporting abrupt presentation of clinical chikungunya-like symptoms. Polymorphisms were identified by TaqMan single-nucleotide polymorphism genotyping assays. Results. After adjustment for sociodemographic risk factors, chikungunya disease was associated with polymorphism in DC-SIGN and TLR3 genes (odds ratios, 5.2 and 3.3, respectively), and TNF-α with reduced persistent joint pain (0.24). Persistent joint pain was also associated with age, female sex and other comorbid conditions. Most interestingly, the Lewis-negative phenotype was strongly associated with both symptomatic chikungunya and immunoglobulin G seropositivity (odds ratios, 2.7, and 3.3, respectively). Conclusion. This study identified polymorphisms in DC-SIGN, TLR3, and TNF-α genes as well as Lewis-negative phenotype as risk factors for chikungunya infection and disease progression.

Research paper thumbnail of Impact of vaccination on the molecular epidemiology and evolution of group A rotaviruses in Latin America and factors affecting vaccine efficacy

Infection, Genetics and Evolution, Aug 1, 2015

hospitalization, RV is still contributing to the burden of diarrhea that persists in hospital set... more hospitalization, RV is still contributing to the burden of diarrhea that persists in hospital settings in sev-33 eral Latin American countries, where RV vaccination is being implemented. Due to the extensive genomic 34 and antigenic diversity, among co-circulating human RV, a major concern has been that the introduction 35 of RV vaccination could exert selection pressure leading to higher prevalence of strains not included in 36 the vaccines and/or emergence of new strains, thus, reducing the efficacy of vaccination. Here we review 37 the molecular epidemiology of RV in Latin America and explore issues of RV evolution and selection in 38 light of vaccination. We further explore etiologies behind the large burden of diarrhea remaining after 39 vaccination in some countries and discuss plausible reasons for vaccine failures.

Research paper thumbnail of Sapovirus: an important cause of acute gastroenteritis in children

The Lancet Child & Adolescent Health, Nov 1, 2019

Sapovirus infections are responsible for both sporadic cases and occasional outbreaks of acute ga... more Sapovirus infections are responsible for both sporadic cases and occasional outbreaks of acute gastroenteritis. While all age groups are affected, children younger than five years of age have the highest burden of disease. Sharing many similarities with closely-related noroviruses, common symptoms of sapovirus gastroenteritis include vomiting and diarrhea, which typically resolve within one week. 1 Sapovirus has also been detected in asymptomatic individuals. 1,2 In recent years, there has been a growing awareness of the importance of sapoviruses to the health of children, due in part to the increasing use of molecular-based diagnostics. Using these diagnostics, sapovirus was detected in 3% to 17% of children with gastroenteritis in high and low-income countries. 2-4 Following rotavirus vaccine introduction in Nicaragua, sapovirus was second only to norovirus as the most commonly detected enteropathogen among children under age five years with gastroenteritis. 5 In this setting, sapovirus was also identified in 15% of children hospitalized for gastroenteritis. 6 Children with sapovirus gastroenteritis are often co-infected with multiple enteric pathogens, especially in low-and middle-income countries (LMIC), which makes it a challenge to understand the true burden of disease. The Malnutrition and Enteric Disease (MAL-ED) study, a multi-site prospective birth cohort study of enteric infections in children in LMIC, used a nested case-control design to estimate pathogen-specific attributable disease burdens. Using this approach, they found sapovirus to have the third highest attributable incidence for

Research paper thumbnail of Vaccine-derived NSP2 segment in rotaviruses from vaccinated children with gastroenteritis in Nicaragua

Infection, Genetics and Evolution, Aug 1, 2012

Rotavirus (RV) vaccination programs have been established in several countries using the humanatt... more Rotavirus (RV) vaccination programs have been established in several countries using the humanattenuated G1P[8] monovalent vaccine Rotarix ™ (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] pentavalent vaccine RotaTeq ™ (Merck). The efficacy of both vaccines is high (~90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007-2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11 G1P[8], 1 G3P[8]) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1P[8] viruses and the single G3P[8] virus had genome constellations typical of human G1P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P[8] RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggests that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs.

Research paper thumbnail of Understanding Asymptomatic Norovirus Infections

EClinicalMedicine, Aug 1, 2018

Research paper thumbnail of The seroprevalence of<i>Taenia solium</i>cysticercosis among epileptic patients in León, Nicaragua, as evaluated by ELISA and western blotting

Annals of Tropical Medicine and Parasitology, 2005

Abstract: The Taenia solium taeniasis/cysticercosis complex is an important public-health problem... more Abstract: The Taenia solium taeniasis/cysticercosis complex is an important public-health problem in several countries, where many epileptic seizures appear to be associated with neurocysticercosis. As few data on this problem in Nicaragua exist, the seroprevalence of ...

Research paper thumbnail of Immune Imprinting Drives Human Norovirus Potential for Global Spread

mBio

In our model, preepidemic human norovirus variants harbor genetic diversification that translates... more In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree.

Research paper thumbnail of Household Surveillance for Norovirus Gastroenteritis in a Nicaraguan Birth Cohort: A Nested Case—Control Analysis of Norovirus Risk Factors

Pathogens, Mar 22, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Large increase of rotavirus diarrhoea in the hospital setting associated with emergence of G12 genotype in a highly vaccinated population in Nicaragua

Clinical Microbiology and Infection, Jun 1, 2015

Rotaviruses (RVs) are a major cause of severe diarrhoea in young children. Nicaragua introduced r... more Rotaviruses (RVs) are a major cause of severe diarrhoea in young children. Nicaragua introduced routine immunization with the pentavalent RV vaccine (RV5) in 2006, which greatly reduced the incidence of diarrhoea. A remaining concern has been the possible emergence of new RV strains to which the vaccination has less effect. In this study, 837 children with diarrhoea in hospital settings were investigated for RV between May 2011 and July 2013. RVs were subsequently typed by multiplex PCR and/or sequencing. Fecal anti-RV IgA titres for a subset of RV-infected (n = 137) and noninfected children (n = 52) were determined with an in-house enzyme-linked immunosorbent assay. The RV detection rate was 8% in 2011, followed by a sharp increase to 29% in 2012 and 19% in 2013. This was associated with emergence and predominance of genotype G12 RV, from 0% in 2011 to 66% in 2012 and 82% in 2013, infecting children from 1 month to 10 years of age. Two sequenced G12 strains showed a Wa-like genome with genotype G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1, similar to the globally emerging G12 strains. Fecal anti-RV IgA analysis showed that most G12-infected and noninfected children had been in contact with either vaccine or wild RV strains, but such antibodies did not prevent symptomatic G12 infection. A marked increase of RV was evident in the hospital setting associated with a nationwide emergence and predominance of RV G12 genotype in a population with high RV5 vaccine coverage.

Research paper thumbnail of Genetic susceptibility to symptomatic norovirus infection in Nicaragua

Journal of Medical Virology, Apr 1, 2009

Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in... more Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in populations from Europe, Asia, and USA. In this study, we have investigated if histo-blood group antigens can predict susceptibility to diarrhea caused by NoV in Nicaragua, Central America, and if this can be reflected in antibodyprevalence and titer to NoV among individuals with different histo-blood group antigen phenotypes. Investigation of 28 individuals infected with NoV and 131 population controls revealed 6% of non-secretors in the population and nil non-secretors among patients infected with NoV, suggesting that non-secretors may be protected against NoV disease in Nicaragua. Surprisingly, 25% of the population was Lewis negative (Le aÀbÀ). NoV infections with genogroup I (GI) and GII occurred irrespective of Lewis genotype, but none of the Lewis a positive (Le a þ bÀ) were infected. The globally dominating GII.4 virus infected individuals of all blood groups except AB (n ¼ 5), while the GI viruses (n ¼ 4) infected only blood type O individuals. Furthermore, O blood types were susceptible to infections with GI.4, GII.4, GII.7, GII.17, and GII.18-Nica viruses, suggesting that secretors with blood type O are susceptible (OR ¼ 1.52) and non-secretors resistant. The overall antibody-prevalence to NoV GII.3 VLP was 62% with the highest prevalence among blood type B carriers (70%) followed by A (68%) and O (62%). All four investigated individuals carrying blood type AB were antibody-negative. Among secretors, 63% were antibody-positive compared to 33% among non-secretors (P ¼ 0.151). This study extends previous knowledge about the histo-blood group antigens role in NoV disease in a population with different genetic background than North American and European.

Research paper thumbnail of Risk Factors and Clinical Profile of Sapovirus-associated Acute Gastroenteritis in Early Childhood: A Nicaraguan Birth Cohort Study

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2021

Background: Sapovirus is increasingly recognized as an important cause of acute gastroenteritis (... more Background: Sapovirus is increasingly recognized as an important cause of acute gastroenteritis (AGE) in children. We identified risk factors and characterized the clinical profile of sapovirus AGE in a birth cohort in León, Nicaragua. Methods: We conducted a case-control study nested within a birth cohort (n=444). Fieldworkers conducted weekly household AGE surveillance. AGE stools were tested for sapovirus by RT-qPCR. For each first sapovirus episode, we selected two healthy age-matched controls and estimated independent risk factors of sapovirus AGE using conditional logistic regression. We compared clinical characteristics of sapovirus AGE episodes with episodes associated with other etiologies, and identified co-infections with other enteric pathogens.

Research paper thumbnail of Clinical characteristics, risk factors, and population attributable fraction for campylobacteriosis in a nicaraguan birth cohort

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2021

Campylobacteriosis is an important contributor to the global burden of acute gastroenteritis (AGE... more Campylobacteriosis is an important contributor to the global burden of acute gastroenteritis (AGE). In Nicaragua, the burden, risk factors, and species diversity for infant campylobacteriosis are unknown. Between June 2017 and December 2018, we enrolled 444 infants from León, Nicaragua, in a population-based birth cohort, conducting weekly household AGE surveillance. First, we described clinical characteristics of symptomatic Campylobacter infections, and then compared clinical characteristics between Campylobacter jejuni/coli and non-jejuni/coli infections. Next, we conducted a nested case-control analysis to examine campylobacteriosis risk factors. Finally, we estimated the population attributable fraction of campylobacteriosis among infants experiencing AGE. Of 296 AGE episodes in the first year of life, Campylobacter was detected in 59 (20%), 39 were C. jejuni/coli, and 20 were non-jejuni/coli species, including the first report of Campylobacter vulpis infection in humans. Acute gastroenteritis symptoms associated with C. jejuni/coli lasted longer than those attributed to other Campylobacter species. In a conditional logistic regression model, chickens in the home (odds ratio [OR]: 3.8, 95% CI: 1.4-9.8), a prior AGE episode (OR: 3.3; 95% CI: 1.4-7.8), and poverty (OR: 0.4; 95% CI: 0.2-0.9) were independently associated with campylobacteriosis. Comparing 90 infants experiencing AGE with 90 healthy controls, 22.4% (95% CI: 11.2-32.1) of AGE episodes in the first year of life could be attributed to Campylobacter infection. Campylobacter infections contribute substantially to infant AGE in León, Nicaragua, with non-jejuni/ coli species frequently detected. Reducing contact with poultry in the home and interventions to prevent all-cause AGE may reduce campylobacteriosis in this setting.

Research paper thumbnail of Zika RNA and Flavivirus-Like Antigens in the Sperm Cells of Symptomatic and Asymptomatic Subjects

Viruses, Jan 21, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Risk Factors for Norovirus Gastroenteritis among Nicaraguan Children

American Journal of Tropical Medicine and Hygiene, Sep 7, 2017

Norovirus is a leading cause of pediatric gastroenteritis. Understanding norovirus epidemiology i... more Norovirus is a leading cause of pediatric gastroenteritis. Understanding norovirus epidemiology is essential for reducing disease burden. We conducted a case-control study to describe the distribution, clinical features, and risk factors of norovirus gastroenteritis among children < 5 years of age in León, Nicaragua. Cases were children testing positive for norovirus and controls were children living in the cases' communities. Study staff interviewed mothers of enrolled cases and controls to obtain detailed exposure information including food, water, and sanitation sources; recent exposures; household characteristics; and handwashing practices. In addition, study staff requested stool samples to be tested for norovirus from select household members. We used descriptive statistics to understand the epidemiologic and clinical features of gastroenteritis episodes. To analyze potential risk factors, we used Firth's penalized logistic regression to estimate crude and adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). There were 102 children with gastroenteritis, 18 cases of norovirus and 31 controls. Norovirus cases occurred later in the year, corresponding to a delay in the rainy season. Cases were more likely to have a household member with norovirus in their stool as compared with controls [crude OR: 13.3 (95% CI: 2.5, 136.2) and adjusted OR: 11.5 (95% CI: 1.6, 223.2)]. In addition, alcohol-based hand sanitizer use among household members was reported for 10 (32%) of controls and but never for cases. Further research is needed to understand household transmission of norovirus in low-and middle-income countries and the potential impact of hand sanitizer use.