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.

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.

Dengue severity by serotype and immune status in 19 years of pediatric clinical studies in Nicaragua.

BACKGROUND: Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease. METHODS: This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the relationship of serotype and immune status with dengue severity. Dengue cases were confirmed by molecular, serological, and/or virological methods, and sudy participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients. RESULTS: We enrolled a total of 15,266 participants, of whom 3,227 (21%) were positive for DENV infection. Of 2,630 cases with serotype result by RT-PCR, 557 corresponded to DENV1, 992 to DENV2, 759 to DENV3 and 322 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 caused a higher proportion of severe disease compared to other serotypes, whereas DENV3 caused the greatest percentage of severity according to the WHO-2009 classification. DENV2 was associated with increased odds of pleural effusion and low platelet count, while DENV3 was associated with both hypotensive and compensated shock. CONCLUSIONS: These findings demonstrate differences in dengue severity by serotype and immune status and emphasize the critical need for a dengue vaccine with balanced effectiveness against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and serostatus.

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.

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.

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.

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.

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.

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.

Symptoms, Infection Duration, and Hemagglutinin Inhibition Antibody Response in Influenza A Infections.

BACKGROUND: Many influenza studies assume that symptomatic and asymptomatic cases have equivalent antibody responses. METHODS: This study examines the relationship between influenza symptoms and serological response. Influenza-positive index cases and household members in Managua, Nicaragua, during 2012-2017 were categorized by symptom status. RESULTS: Antibody response was assessed using hemagglutination inhibition assays (HAI). Among 510 cases, 74.5% had ≥4-fold increase in HAI antibodies, and 75.3% had febrile illness. In a logistic regression model, febrile cases had 2.17 times higher odds of a ≥4-fold titer rise compared to asymptomatic cases (95% confidence interval, 1.02-4.64). CONCLUSIONS: Studies relying on serological assays may not generalize to asymptomatic infections.

Pneumonia Following Symptomatic Influenza Infection Among Nicaraguan Children Before and After Introduction of the Pneumococcal Conjugate Vaccine.

Influenza is associated with primary viral and secondary bacterial pneumonias; however, the dynamics of this relationship in populations with varied levels of pneumococcal vaccination remain unclear. We conducted nested matched case-control studies in 2 prospective cohorts of Nicaraguan children aged 2-14 years: 1 before pneumococcal conjugate vaccine introduction (2008-2010) and 1 following introduction and near universal adoption (2011-2018). The association between influenza and pneumonia was similar in both cohorts. Participants with influenza (across types/subtypes) had higher odds of developing pneumonia in the month following influenza infection. These findings underscore the importance of considering influenza in interventions to reduce global pneumonia burden.

Zika virus infection enhances future risk of severe dengue disease.

The Zika pandemic sparked intense interest in whether immune interactions among dengue virus serotypes 1 to 4 (DENV1 to -4) extend to the closely related Zika virus (ZIKV). We investigated prospective pediatric cohorts in Nicaragua that experienced sequential DENV1 to -3 (2004 to 2015), Zika (2016 to 2017), and DENV2 (2018 to 2020) epidemics. Risk of symptomatic DENV2 infection and severe disease was elevated by one prior ZIKV infection, one prior DENV infection, or one prior DENV infection followed by one ZIKV infection, compared with being flavivirus-naïve. By contrast, multiple prior DENV infections reduced dengue risk. Further, although high preexisting anti-DENV antibody titers protected against DENV1, DENV3, and ZIKV disease, intermediate titers induced by previous ZIKV or DENV infection enhanced future risk of DENV2 disease and severity, as well as DENV3 severity. The observation that prior ZIKV infection can modulate dengue disease severity like a DENV serotype poses challenges to development of dengue and Zika vaccines.

Assessing the Incidence of Symptomatic Respiratory Syncytial Virus Illness Within a Prospective Birth Cohort in Managua, Nicaragua.

BACKGROUND: Respiratory syncytial virus (RSV) causes substantial morbidity and mortality among children worldwide, commonly through acute lower respiratory tract infections (ALRI). To assess the incidence rate of symptomatic RSV illness among young children, we conducted a prospective birth cohort study following children from 0-2 years of age in Managua, Nicaragua. METHODS: Children meeting the testing criteria (fever, history of fever, or severe respiratory symptoms [apnea, stridor, nasal flaring, wheezing, chest indrawing, and/or central cyanosis]) were tested for RSV infections using real-time reverse transcriptase-polymerase chain reaction. An acute lower respiratory infection was defined as a diagnosis of pneumonia, bronchiolitis, bronchitis, or bronchial hyperreactivity. The incidence rate was calculated, and 95% confidence intervals were estimated using a Poisson distribution. RESULTS: A total of 833 children participated in the cohort: 289 (34.7%) had at least 1 episode of laboratory-confirmed RSV, and 156 (18.7%) of had an episode of RSV-associated ALRI (RSV-ALRI). The incidence rate of symptomatic RSV was 248.1 cases per 1000 person-years (95% confidence interval [CI] 223.2-275.7). While infants aged 6-11 months had the highest incidence of symptomatic RSV (361.3/1000 person-years, 95% CI 304.4-428.8), infants <3 months had the highest incidence of severe RSV (RSV-associated hospitalizations and/or severe ALRI). RSV was also associated with 25.0-37.5% of deaths from medical causes (n = 8). CONCLUSIONS: A substantial burden of RSV exists among children aged <2 years in Nicaraguan communities. RSV was also a leading cause of infant mortality among study participants. The development and implementation of effective RSV prevention and treatment measures represent an opportunity to substantially reduce severe illness and death among children worldwide.