Correction: SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children.

[This corrects the article DOI: 10.1371/journal.pgph.0000414.].

Obesity Is Associated With Increased Pediatric Dengue Virus Infection and Disease: A 9-Year Cohort Study in Managua, Nicaragua.

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.

Tracking the genetic diversity of SARS-CoV-2 variants in Nicaragua throughout the COVID-19 Pandemic.

The global circulation of SARS-CoV-2 has been extensively documented, yet the dynamics within Central America, particularly Nicaragua, remain underexplored. This study characterizes the genomic diversity of SARS-CoV-2 in Nicaragua from March 2020 through December 2022, utilizing 1064 genomes obtained via next-generation sequencing. These sequences were selected nationwide and analyzed for variant classification, lineage predominance, and phylogenetic diversity. We employed both Illumina and Oxford Nanopore Technologies for all sequencing procedures. Results indicated a temporal and spatial shift in dominant lineages, initially from B.1 and A.2 in early 2020 to various Omicron subvariants towards the study's end. Significant lineage shifts correlated with changes in COVID-19 positivity rates, underscoring the epidemiological impact of variant dissemination. The comparative analysis with regional data underscored the low diversity of circulating lineages in Nicaragua and their delayed introduction compared to other countries in the Central American region. The study also linked specific viral mutations with hospitalization rates, emphasizing the clinical relevance of genomic surveillance. This research advances the understanding of SARS-CoV-2 evolution in Nicaragua and provide valuable information regarding its genetic diversity for public health officials in Central America. We highlight the critical role of ongoing genomic surveillance in identifying emergent lineages and informing public health strategies.

Primary exposure to Zika virus is linked with increased risk of symptomatic dengue virus infection with serotypes 2, 3, and 4, but not 1.

Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on preexisting antibodies and infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) is associated with increased risk of DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by DENV1-4 in a pediatric Nicaraguan cohort. Of 3412 participants in 2022, 10.6% experienced dengue cases caused by DENV1 (n = 139), DENV4 (n = 133), DENV3 (n = 54), DENV2 (n = 9), or an undetermined serotype (n = 39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since last infection, and year, and repeat measurements were used to predict disease risk. Compared with flavivirus-naïve participants, primary ZIKV infection was associated with increased risk of disease caused by DENV4 (relative risk = 2.62, 95% confidence interval: 1.48 to 4.63) and DENV3 (2.90, 1.34 to 6.27), but not DENV1 infection. Primary DENV infection or DENV followed by ZIKV infection was also associated with increased risk of DENV4 disease. We reanalyzed 19 years of cohort data and demonstrated that prior flavivirus immunity and antibody titer had distinct associations with disease risk depending on incoming serotype. We thus find that prior ZIKV infection, like prior DENV infection, is associated with increased risk of disease with certain DENV serotypes. Cross-reactivity among flaviviruses should be considered when assessing vaccine safety and efficacy.

Obesity is associated with increased pediatric dengue virus infection and disease: A 9-year cohort study in Managua, Nicaragua.

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 the 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 5,940 children in the Pediatric Dengue Cohort Study in Nicaragua to examine 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 pre-infection DENV antibody titers. Results: From 2011 to 2019, children contributed 26,273 person-years of observation, and we observed an increase in the prevalence of overweight (from 12% to 17%) and obesity (from 7% to 13%). There were 1,682 DENV infections and 476 dengue cases in the study population. Compared to 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 disease given infection (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, independently of age, sex, and pre-infection DENV antibody titers.

Serotype-Specific Epidemiological Patterns of Inapparent versus Symptomatic Primary Dengue Virus Infections: A 17-year cohort study in Nicaragua.

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 multiplex 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). First, we evaluated the performance of the EDIII-MMBA with samples characterized by RT-PCR or focus reduction neutralization test. Next, we analyzed 46% (N=574) of total 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 neighborhood into account. Infection incidence and percentage of inapparent, symptomatic, and severe infections were analyzed by serotype. The EDIII-MMBA demonstrated excellent overall accuracy (100%, 95.8-100%) for serotyping symptomatic and inapparent primary DENV infections when evaluated against gold-standard serotyping methods. We found that a significant majority of primary infections were inapparent, with DENV3 exhibiting the highest likelihood of symptomatic and severe primary infections (Pooled OR compared to DENV1 = 2.13, 95% CI 1.28-3.56, and 6.75, 2.01-22.62, respectively), whereas DENV2 was similar to DENV1 in both analyses. Significant within- 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. 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 significant differences in infection outcomes by serotype emphasizes the need for vaccines with balanced immunogenicity and efficacy across serotypes.

Longitudinal analysis of post-acute chikungunya-associated arthralgia in children and adults: A prospective cohort study in Managua, Nicaragua (2014-2018).

Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To characterize long-term chikungunya-associated arthralgia, we recruited 770 patients (105 0-4 years old [y/o], 200 5-9 y/o, 307 10-15 y/o, and 158 16+ y/o) with symptomatic chikungunya virus infections in Managua, Nicaragua, during two consecutive chikungunya epidemics (2014-2015). Participants were assessed at ~15 days and 1, 3, 6, 12, and 18 months post-fever onset. Following clinical guidelines, we defined participants by their last reported instance of arthralgia as acute (≤10 days post-fever onset), interim (>10 and <90 days), or chronic (≥90 days) cases. We observed a high prevalence of arthralgia (80-95%) across all ages over the study period. Overall, the odds of acute arthralgia increased in an age-dependent manner, with the lowest odds of arthralgia in the 0-4 y/o group (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.14-0.51) and the highest odds of arthralgia in the 16+ y/o participants (OR: 4.91, 95% CI: 1.42-30.95) relative to 10-15 y/o participants. Females had higher odds of acute arthralgia than males (OR: 1.63, 95% CI: 1.01-2.65) across all ages. We found that 23-36% of pediatric and 53% of adult participants reported an instance of post-acute arthralgia. Children exhibited the highest prevalence of post-acute polyarthralgia in their legs, followed by the hands and torso - a pattern not seen among adult participants. Further, we observed pediatric chikungunya presenting in two distinct phases: the acute phase and the subsequent interim/chronic phases. Thus, differences in the presentation of arthralgia were observed across age, sex, and disease phase in this longitudinal chikungunya cohort. Our results elucidate the long-term burden of chikungunya-associated arthralgia among pediatric and adult populations.

Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1.

Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre-existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy.

Longitudinal Analysis of the Burden of Post-Acute Chikungunya-Associated Arthralgia in Children and Adults: A Prospective Cohort Study in Managua, Nicaragua (2014-2019).

Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To characterize long-term chikungunya-associated arthralgia, we recruited 770 patients (105 0-4 year olds [y/o], 200 5-9 y/o, 307 10-15 y/o, and 158 16+ y/o) with symptomatic chikungunya virus infections in Managua, Nicaragua, during two chikungunya epidemics (2014-2015). Participants were assessed at ~15 days and 1, 3, 6, 12, and 18 months post-fever onset. Following clinical guidelines, we defined participants by their last reported instance of arthralgia as acute (≤10 days post-fever onset), interim (>10 and <90 days), or chronic (≥90 days) cases. We observed a high prevalence of arthralgia (80-95%) across all ages over the study period. Overall, the odds of acute arthralgia increased in an age-dependent manner, with the lowest odds of arthralgia in the 0-4 y/o group (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.14-0.51) and the highest odds of arthralgia in the 16+ y/o participants (OR: 4.91, 95% CI: 1.42-30.95) relative to 10-15 y/o participants. Females had a higher odds of acute arthralgia than males (OR: 1.63, 95% CI: 1.01-2.65) across all ages. We found that 23-36% of pediatric and 53% of adult participants reported an instance of post-acute arthralgia. Children exhibited the highest prevalence of post-acute polyarthralgia in their legs, followed by the hands and torso - a pattern not seen among adult participants. Further, we observed pediatric chikungunya presenting in two distinct phases: the acute phase and the associated interim and chronic phases. Differences in the presentation of arthralgia were observed across age, sex, and disease phase in this longitudinal chikungunya cohort. Our results elucidate the long-term burden of chikungunya-associated arthralgia among pediatric and adult populations.

Infection-Induced Immunity Is Associated With Protection Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Decreased Infectivity.

BACKGROUND: The impact of infection-induced immunity on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has not been well established. Here we estimate the effects of prior infection induced immunity in adults and children on SARS-CoV-2 transmission in households. METHODS: We conducted a household cohort study from March 2020-November 2022 in Managua, Nicaragua; following a housheold SARS-CoV-2 infection, household members are closely monitored for infection. We estimate the association of time period, age, symptoms, and prior infection with secondary attack risk. RESULTS: Overall, transmission occurred in 70.2% of households, 40.9% of household contacts were infected, and the secondary attack risk ranged from 8.1% to 13.9% depending on the time period. Symptomatic infected individuals were more infectious (rate ratio [RR] 21.2, 95% confidence interval [CI]: 7.4-60.7) and participants with a prior infection were half as likely to be infected compared to naïve individuals (RR 0.52, 95% CI:.38-.70). In models stratified by age, prior infection was associated with decreased infectivity in adults and adolescents (secondary attack risk [SAR] 12.3, 95% CI: 10.3, 14.8 vs 17.5, 95% CI: 14.8, 20.7). However, although young children were less likely to transmit, neither prior infection nor symptom presentation was associated with infectivity. During the Omicron era, infection-induced immunity remained protective against infection. CONCLUSIONS: Infection-induced immunity is associated with decreased infectivity for adults and adolescents. Although young children are less infectious, prior infection and asymptomatic presentation did not reduce their infectivity as was seen in adults. As SARS-CoV-2 transitions to endemicity, children may become more important in transmission dynamics.

Burden and seasonality of primary and secondary symptomatic common cold coronavirus infections in Nicaraguan children.

BACKGROUND: The current SARS-CoV-2 pandemic highlights the need for an increased understanding of coronavirus epidemiology. In a pediatric cohort in Nicaragua, we evaluate the seasonality and burden of common cold coronavirus (ccCoV) infection and evaluate likelihood of symptoms in reinfections. METHODS: Children presenting with symptoms of respiratory illness were tested for each of the four ccCoVs (NL63, 229E, OC43, and HKU1). Annual blood samples collected before ccCoV infection were tested for antibodies against each ccCoV. Seasonality was evaluated using wavelet and generalized additive model (GAM) analyses, and age-period effects were investigated using a Poisson model. We also evaluate the risk of symptom presentation between primary and secondary infections. RESULTS: In our cohort of 2576 children from 2011 to 2016, we observed 595 ccCoV infections and 107 cases of ccCoV-associated lower respiratory infection (LRI). The overall incidence rate was 61.1 per 1000 person years (95% confidence interval (CI): 56.3, 66.2). Children under two had the highest incidence of ccCoV infections and associated LRI. ccCoV incidence rapidly decreases until about age 6. Each ccCoV circulated throughout the year and demonstrated annual periodicity. Peaks of NL63 typically occurred 3 months before 229E peaks and 6 months after OC43 peaks. Approximately 69% of symptomatic ccCoV infections were secondary infections. There was slightly lower risk (rate ratio (RR): 0.90, 95% CI: 0.83, 0.97) of LRI between secondary and primary ccCoV infections among participants under the age of 5. CONCLUSIONS: ccCoV spreads annually among children with the greatest burden among ages 0-1. Reinfection is common; prior infection is associated with slight protection against LRI among the youngest children.

The Nicaraguan Pediatric Influenza Cohort Study, 2011-2019: Influenza Incidence, Seasonality, and Transmission.

BACKGROUND: Children account for a large portion of global influenza burden and transmission, and a better understanding of influenza in children is needed to improve prevention and control strategies. METHODS: To examine the incidence and transmission of influenza we conducted a prospective community-based study of children aged 0-14 years in Managua, Nicaragua, between 2011 and 2019. Participants were provided with medical care through study physicians and symptomatic influenza was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). Wavelet analyses were used to examine seasonality. Generalized growth models (GGMs) were used to estimate effective reproduction numbers. RESULTS: From 2011 to 2019, 3016 children participated, with an average of ∼1800 participants per year and median follow-up time of 5 years per child, and 48.3% of the cohort in 2019 had been enrolled their entire lives. The overall incidence rates per 100 person-years were 14.5 symptomatic influenza cases (95% confidence interval [CI]: 13.9-15.1) and 1.0 influenza-associated acute lower respiratory infection (ALRI) case (95% CI: .8-1.1). Symptomatic influenza incidence peaked at age 9-11 months. Infants born during peak influenza circulation had lower incidence in the first year of their lives. The mean effective reproduction number was 1.2 (range 1.02-1.49), and we observed significant annual patterns for influenza and influenza A, and a 2.5-year period for influenza B. CONCLUSIONS: This study provides important information for understanding influenza epidemiology and informing influenza vaccine policy. These results will aid in informing strategies to reduce the burden of influenza.

SARS-CoV-2 infection-induced immunity and the duration of viral shedding: Results from a Nicaraguan household cohort study.

BACKGROUND: Much of the world's population has been infected with SARS-CoV-2. Thus, immunity from prior infection will play a critical role in future SARS-CoV-2 transmission. We investigated the impact of infection-induced immunity on viral shedding duration and viral load. METHODS: We conducted a household cohort study in Managua, Nicaragua, with an embedded transmission study that closely monitors participants regardless of symptoms. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity, respectively. Blood samples were collected twice annually and surrounding household intensive monitoring periods. We used accelerated failure time models to compare shedding times. Participants vaccinated ≥14 days prior to infection were excluded from primary analyses. RESULTS: There were 600 RT-PCR-confirmed SARS-CoV-2 infections in unvaccinated participants between May 1, 2020, and March 10, 2022, with prior ELISA data. Prior infection was associated with 48% shorter shedding times (event time ratio [ETR] 0.52, 95% CI: 0.39-0.69, mean shedding: 13.7 vs. 26.4 days). A fourfold higher anti-SARS-CoV-2 spike titer was associated with 17% shorter shedding (ETR 0.83, 95% CI: 0.78-0.90). Similarly, maximum viral loads (lowest cycle threshold [CT]) were lower for previously infected individuals (mean CT 29.8 vs. 28.0, p = 4.02 × 10-3 ), for adults and children ≥10 years, but not for children 0-9 years; there was little difference in CT levels for previously infected versus naïve adults aged above 60 years. CONCLUSIONS: Prior infection-induced immunity was associated with shorter viral shedding and lower viral loads, which may be important in the transition from pandemic to endemicity.

Pediatric burden and seasonality of human metapneumovirus over 5 years in Managua, Nicaragua.

BACKGROUND: Human metapneumovirus (hMPV) is an important cause of pediatric respiratory infection. We leveraged the Nicaraguan Pediatric Influenza Cohort Study (NPICS) to assess the burden and seasonality of symptomatic hMPV infection in children. METHODS: NPICS is an ongoing prospective study of children in Managua, Nicaragua. We assessed children for hMPV infection via real-time reverse-transcription polymerase chain reaction (RT-PCR). We used classical additive decomposition analysis to assess the temporal trends, and generalized growth models (GGMs) were used to estimate effective reproduction numbers. RESULTS: From 2011 to 2016, there were 564 hMPV symptomatic infections, yielding an incidence rate of 5.74 cases per 100 person-years (95% CI 5.3, 6.2). Children experienced 3509 acute lower respiratory infections (ALRIs), of which 160 (4.6%) were associated with hMPV infection. Children under the age of one had 55% of all symptomatic hMPV infections (62/112) develop into hMPV-associated ALRIs and were five times as likely as children over one to have an hMPV-associated ALRI (rate ratio 5.5 95% CI 4.1, 7.4 p < 0.001). Additionally, symptomatic reinfection with hMPV was common. In total, 87 (15%) of all observed symptomatic infections were detected reinfections. The seasonality of symptomatic hMPV outbreaks varied considerably. From 2011 to 2016, four epidemic periods were observed, following a biennial seasonal pattern. The mean ascending phase of the epidemic periods were 7.7 weeks, with an overall mean estimated reproductive number of 1.2 (95% CI 1.1, 1.4). CONCLUSIONS: Symptomatic hMPV infection was associated with substantial burden among children in the first year of life. Timing and frequency of symptomatic hMPV incidence followed biennial patterns.

SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children.

It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.

Epidemiologic Features of Acute Pediatric Diarrhea in Managua, Nicaragua, from 2011 to 2019.

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.

Association of SARS-CoV-2 Seropositivity and Symptomatic Reinfection in Children in Nicaragua.

Importance: The impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their risk of reinfection is crucial, as they will be among the last groups vaccinated. Objective: To characterize the burden of COVID-19 and assess how risk of symptomatic reinfection may vary by age among children. Design, Setting, and Participants: In this prospective, community-based pediatric cohort study conducted from March 1, 2020, to October 15, 2021, 1964 nonimmunocompromised children aged 0 to 14 years were enrolled by random selection from the Nicaraguan Pediatric Influenza Cohort, a community-based cohort in District 2 of Managua, Nicaragua. Additional newborn infants aged 4 weeks or younger were randomly selected and enrolled monthly via home visits. Exposures: Prior COVID-19 infection as confirmed by positive anti-SARS-CoV-2 antibodies (receptor binding domain and spike protein) or real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19 infection at least 60 days before current COVID-19 infection. Main Outcomes and Measures: Symptomatic COVID-19 cases confirmed by real-time RT-PCR and hospitalization within 28 days of symptom onset of a confirmed COVID-19 case. Results: This cohort study assessed 1964 children (mean [SD] age, 6.9 [4.4] years; 985 [50.2%] male). Of 1824 children who were tested, 908 (49.8%; 95% CI, 47.5%-52.1%) were seropositive during the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (5.8%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children younger than 2 years (16.1 cases per 100 person-years; 95% CI, 12.5-20.5 cases per 100 person-years), which was approximately 3 times the incidence rate in any other child age group assessed. In addition, 41 symptomatic SARS-CoV-2 episodes (19.8%; 95% CI, 14.4%-25.2%) were reinfections. Conclusions and Relevance: In this prospective, community-based pediatric cohort study, rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing at approximately 5 years of age. In addition, symptomatic reinfections represented a large proportion of symptomatic COVID-19 cases.

Homotypic protection against influenza in a pediatric cohort in Managua, Nicaragua.

The period of protection from repeat infection following symptomatic influenza is not well established due to limited availability of longitudinal data. Using data from a pediatric cohort in Managua, Nicaragua, we examine the effects of natural influenza virus infection on subsequent infection with the same influenza virus subtype/lineage across multiple seasons, totaling 2,170 RT-PCR-confirmed symptomatic influenza infections. Logistic regression models assessed whether infection in the prior influenza season protected against homologous reinfection. We sequenced viruses from 2011-2019 identifying dominant clades and measuring antigenic distances between hemagglutinin clades. We observe homotypic protection from repeat infection in children infected with influenza A/H1N1pdm (OR 0.12, CI 0.02-0.88), A/H3N2 (OR 0.41, CI 0.24-0.73), and B/Victoria (OR 0.00, CI 0.00-0.14), but not with B/Yamagata viruses (OR 0.60, CI 0.09-2.10). Overall, protection wanes as time or antigenic distance increases. Individuals infected with one subtype or lineage of influenza virus have significantly lower odds of homologous reinfection for the following one to two years; after two years this protection wanes. This protection is demonstrated across multiple seasons, subtypes, and lineages among children.

SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children.

It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.