BACKGROUND:Although the hemagglutination inhibition (HAI) titer remains the gold standard correlate of protection against influenza, it does not fully capture the broader antibody responses that contribute to immunity. METHODS:We analyzed immune responses in paired pre-infection and convalescent sera from 306 RT-PCR-confirmed A(H3N2) infections from two household studies (2014-2018) in Managua, Nicaragua. Antibody responses were measured by HAI and enzyme-linked immunosorbent assays (ELISAs) against full-length hemagglutinin (HA), the HA stalk, and neuraminidase (NA). Participants were classified as HAI responders (≥ 4-fold HAI rise), alternate responders (no HAI rise but ≥ 4-fold boost in ≥ 1 ELISA), or no-response individuals (no ≥ 4-fold rise in any assay). We compared demographic, clinical, and pre-infection antibody characteristics across these groups. We also analyzed predictors of an NA response. RESULTS:Overall, 77% of participants had HAI seroconversion or a fourfold rise. Among the 23% HAI non-responders, 62% had alternate antibody responses. No-response individuals had the highest pre-infection HAI and full-length HA titers (p < 0.01), the lowest viral loads, and the lowest frequency of fever or influenza-like illness symptoms (p < 0.01). An NA response was more common among symptomatic individuals and moderate baseline titers, with both low and high extremes reducing NA response odds. CONCLUSIONS:High baseline HAI titers can limit detectable fourfold rises and are associated with milder illness. Evaluating additional immune responses may capture a more complete picture of the host response to infection, thereby improving surveillance and informing vaccine development.

The role of undernutrition on influenza virus shedding is unclear. We assessed stunting, an indicator of chronic undernutrition, as a predictor of shedding duration in children in the Household Influenza Cohort Study, in Managua, Nicaragua. Stunted children, aged 3–9 years, shed influenza longer than their nonstunted peers. In sub-group analysis, associations were driven by H3N2 and influenza B (IB) infections. Analysis of cycle threshold (Ct) values showed slower clearance of IB viruses in stunted children. These findings suggest undernutrition may prolong influenza shedding, with implications for transmission dynamics and control strategies in low- and middle-income countries where stunting remains prevalent.

SARS-CoV-2 reinfections have increased since Omicron and are common. Yet, as we approach endemicity, the frequency, severity, and consequences of reinfections remain poorly understood. Using data from a household transmission study in Managua, Nicaragua (2020-2024), we evaluated protection conferred by one, two, and three+ prior infections and compared the severity of first, second, and third+ RT-PCR-confirmed SARS-CoV-2 infections. Compared to those with no prior infections, one, two, and three+ prior infections were associated with increasing protection from symptomatic infection, with incidence rate ratios of 0.39, (95% Confidence Interval [CI]: 0.26-0.61), 0.24 (95%CI: 0.13-0.42), and 0.20 (95%CI: 0.09-0.42), respectively. Among RT-PCR-confirmed infections, reinfections were associated with decreased severity; compared with first infections, second infections had 1.57 (95%CI: 1.15-2.16) times the proportion of subclinical disease and 0.65 (95%CI: 0.49-0.86) times the proportion of moderate/severe disease. Our findings suggest that protection generated from two prior infections may be stronger than one prior infection, although additional benefit beyond the second infection was not clearly observed. Together, our results suggest we are approaching an endemic phase of SARS-CoV-2 characterized by reduced severity relative to first infections, yet the burden remains high, underscoring the importance of maintaining immunity to manage ongoing disease.

This text is a Spanish translation of the following article: "Assessing the Incidence of Symptomatic Respiratory Syncytial Virus Illness Within a Prospective Birth Cohort in Managua, Nicaragua." It was published by Oxford University Press for the Infectious Diseases Society of America on July 29, 2019: https://doi.org/10.1093/cid/ciz585 Encontramos una carga sustancial de VSR en niños nicaragüenses menores de 2 años. Alrededor de 1/3 de las muertes por causas médicas en este estudio estaban asociadas a infecciones del VSR, lo cual sugiere que este agente es un importante impulsor de la mortalidad infantil en esta población, la cual ha sido vacunada en gran medida y padece poco de malaria o VIH.

Background:Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis is complicated in children and adolescents by their overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared the three diseases. We aimed to identify distinguishing pediatric characteristics of each disease. Methods:Data were derived from laboratory-confirmed cases (symptomatic infections) aged 2-<18 years enrolled in a longitudinal cohort study in Managua, Nicaragua, and attending a primary health care center from January 19, 2006, through December 31, 2023. We collected clinical records and laboratory results across the first 10 days of illness. Data were analyzed with generalized additive models, day-and-disease-specific prevalence estimates, and machine learning models. Findings:We characterized 1,405 dengue, 517 chikungunya, and 522 Zika pediatric cases. We included 1,165 (47·7%) males and 1,279 (52·3%) females, with a median age of 10·0 (IQR 7·0-12·7) years. The prevalence of many clinical features exhibited by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. Dengue cases were differentiated most by abdominal pain (Prevalence difference (PD) 19·1%, 95% confidence interval (CI): 15·7%, 22·9%), leukopenia (PD 41·1%, 95% CI: 36·2%, 45·6%), nausea (PD 15·5%, 95% CI: 12·2%, 19·2%), vomiting (PD 21·9%, 95% CI: 17·9%, 26·1%), and basophilia (PD 42·3%, 95% CI: 37·4%, 47·0%); chikungunya cases were differentiated most by arthralgia (PD 60·5%, 95% CI: 56·3%, 64·2%) and the absence of leukopenia (PD -32·0%, 95% CI: -36·7%, -27·1%) and papular rash (PD -14·9%, 95% CI: -17·2%, -12·7%); and Zika cases were differentiated most by rash (PD 31·8%, 95% CI: 27·0%, 36·2%) and the lack of fever (PD -37·3%, 95% CI: -41·7%, -33·0%) and lymphocytopenia (PD -41·9%, 95% CI: -46·6%, -37·1%). Dengue and chikungunya cases exhibited similar temperature dynamics during acute illness, and their temperatures were higher than Zika cases. Sixty-two laboratory-confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented very similarly to afebrile Zika cases, though some exhibited warning signs of disease severity. The presence of arthralgia, the presence of basophilia, and the absence of fever were the most important model-based distinguishing predictors of chikungunya, dengue, and Zika, respectively. Interpretations:These findings substantially update our understanding of dengue, chikungunya, and Zika in children while identifying various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current guidance. Funding:US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.

Vaccination and prior infection elicit neutralizing antibodies targeting SARS-CoV-2, yet the quantitative relationship between serum antibodies and infection risk against viral variants remains uncertain, particularly in underrepresented regions. We investigated the protective correlation of pre-exposure serum neutralizing antibody levels, employing a panel of SARS-CoV-2 pseudoviruses (Omicron BA.1, Omicron BA.2, and ancestral D614G), and Spike-binding antibody levels, with symptomatic BA.1 or BA.2 SARS-CoV-2 infections and overall infection, in 345 household contacts from a SARS-CoV-2 household cohort study in Nicaragua. A four-fold increase in homotypic-neutralizing (e.g., BA.1-neutralizing vs. BA.1 exposure) titers was correlated with protection from symptomatic infections (BA.1 protection: 28% [95%CI 12-42%]; BA.2 protection: 43% [20-62%]), and ancestral-neutralizing titers were also correlated with protection from either variant, but only at higher average levels than homotypic. Mediation analyses revealed that homotypic and D614G-neutralizing antibodies mediated protection from infection and symptomatic infection both from prior infection and vaccination. These findings underscore the importance of monitoring variant-specific antibody responses and highlight that antibodies targeting circulating strains may be more predictive of protection from infection. Nevertheless, ancestral-strain-neutralizing antibodies remain relevant as a correlate of protection. Our study emphasizes the need for continued efforts to assess antibody correlates of protection.

Immune responses against neuraminidase (NA) and hemagglutinin (HA) are critical for developing effective influenza vaccines, yet their role in influenza transmission remains unclear. We conducted household transmission studies in Managua, Nicaragua, to assess the impact of anti-NA and anti-HA antibodies induced by natural infection on influenza A/H3N2 susceptibility and infectivity. Using mathematical models capturing household transmission dynamics, we found that high pre-existing antibody levels against the HA head (>31, [95% CrI 13-67]), HA stalk (>35, [95% CrI 11-66]), and NA (>31, [95% CrI 12-68]) are associated with reduced susceptibility to infection (relative susceptibility: HA head, 0.63 [95% CrI 0.42-0.98]; HA stalk, 0.66 [95% CrI 0.44-0.99]; NA, 0.49 [95% CrI 0.30-0.76]). HA stalk (>58 [95% CrI: 47-70]) and NA (>27 [95% CrI: 15-43]) are associated with reduced infectivity (relative infectivity: NA, 0.55 [95% CrI: 0.32-0.98], HA stalk 0.53 [95% CrI: 0.27-0.97]). These findings suggest that influenza vaccines designed to elicit NA immunity in addition to HA immunity may not only enhance protection against infection but also reduce onward transmission.

BACKGROUND:Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis of these three diseases is complicated in children and adolescents due to overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared these three diseases. We aimed to use 18 years of primary care observations from a paediatric cohort to characterise the distinguishing features of dengue, chikungunya, and Zika. METHODS:This single-centre prospective cohort study was based on the ongoing Pediatric Dengue Cohort Study (PDCS), which started on Aug 30, 2004, in District II of Managua, Nicaragua. The PDCS was initiated to study dengue virus infections in children who attended the Health Center Sócrates Flores Vivas (HCSFV) for their medical needs; over the years, the PDCS expanded the age range (2 to <10 years expanded to 2 to <18 years). The PDCS also expanded eligibility criteria to include chikungunya virus and Zika virus before they entered the geographical study area in August, 2014 and January, 2016, respectively. For this study, we included laboratory confirmed cases of dengue, chikungunya, and Zika enrolled in the PDCS between Jan 19, 2006, and Dec 31, 2023, and evaluated at the HCSFV. We assessed clinical features (clinical records and laboratory results) during the first 10 days of illness using generalised additive models, day-specific and disease-specific prevalence estimates, and machine learning models. FINDINGS:We characterised 1405 dengue, 517 chikungunya, and 522 Zika cases. The median age was 10·0 years (IQR 7·0-12·7); 1165 (47·7%) cases were male and 1279 (52·3%) were female. The prevalence of many clinical features shown by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. The presence of basophilia (prevalence difference 42·3% [95% CI 37·4 to 47·0]), monocytopenia (13·0% [10·0 to 16·4]), abdominal pain (19·1% [15·7 to 22·9]), and leukopenia (41·1% [36·2 to 45·6]) best distinguished dengue; the presence of arthralgia (60·5% [56·3 to 64·2]) and absence of papular rash (-14·9% [-17·2 to -12·7]), leukopenia (-32·0% [-36·7 to -27·1]), and conjunctival injection (-4·9% [-6·6 to -3·3]) best distinguished chikungunya; and the presence of generalised rash (35·0% [30·1 to 39·7]) and absence of fever (-37·3% [-41·7 to -33·0]), headache (-36·2% [-41·1 to -31·2]), myalgia (-30·1% [-33·9 to -26·2]), and lymphocytopenia (-41·9% [-46·6 to -37·1]) best distinguished Zika. Dengue and chikungunya cases showed similar temperature dynamics during acute illness, and their mean temperatures were higher than Zika cases. 62 laboratory confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented most similarly to afebrile Zika cases, but five (8·1%) had warning signs of dengue disease severity. Based on boosted regression tree models, the presence of arthralgia and absence of basophilia and leukopenia most distinguished chikungunya, the presence of basophilia and leukopenia most distinguished dengue, and the absence of fever most distinguished Zika. INTERPRETATIONS:These findings substantially update the understanding of dengue, chikungunya, and Zika in a paediatric population and identify various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current guidance. FUNDING:US National Institutes of Health. TRANSLATION:For the Spanish translation of the abstract see Supplementary Materials section.

Since the emergence of the antigenically distinct Omicron variant, SARS-CoV-2 reinfections have increased and are common. Yet, as we approach endemicity, the frequency, severity, and consequences of reinfections remain poorly understood. Using data from a household transmission study in Managua, Nicaragua (2020-2024), we evaluated protection conferred by one, two, and three+ prior infections and compared the severity of first, second, and third+ RT-PCR-confirmed SARS-CoV-2 infections. In adults, compared to those with no prior infections, after adjusting for vaccination, one, two, and three+ prior infections were associated with increasing protection from symptomatic infection: 46%, (95% Confidence Interval [CI]: 32-57%), 69% (95%CI: 56-78%), and 77% (95%CI: 58-88%), respectively. Compared to first infections, second and third+ infections were associated with decreasing severity in adults, adjusted for vaccination; 35% (95%CI: 11-52%) and 42% (95%CI: 6-65%) less moderate/severe disease, and 152% (95%CI: 46-336%) and 243% (95%CI: 82-545%) more subclinical disease, respectively.

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 study participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients. Results We enrolled a total of 15,833 participants, of whom 3,308 (21%) were positive for DENV infection. Of 2,644 cases with serotype result by RT-PCR, 559 corresponded to DENV1, 1,002 to DENV2, 760 to DENV3 and 323 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.

AbstractSummaryDengue, a major public health threat, is a viral infection spread by mosquitoes that can cause a range of symptoms from mild to life-threatening. Our study analyzed 19 years of data from two pediatric studies in children 2 to 17 years of age in Managua, Nicaragua. We aimed to understand how dengue severity varies with different serotypes of dengue virus (DENV1-4) and whether the child had a previous dengue infection. We found that DENV2 and DENV3 caused the most sever disease in children. DENV3 lead to sever outcomes in both primary (first-time) and secondary (repeat) infections, while DENV2 is particularly severe in secondary infections. These findings highlight the importance of a balanced dengue vaccine that can protect against all four virus strains, as current vaccines show varying effectiveness. Our research emphasizes the need for effective prevention and treatment strategies to manage dengue, particularly in regions where the virus is widespread.BackgroundDengue 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.MethodsThis 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.ResultsWe 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.ConclusionsThese 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.

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

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.

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.

Abstract Background: Gaps remain in our knowledge of the humoral correlates of protection against influenza A/H3N2, including the role of antibodies against the hemagglutinin stalk, a highly conserved but immunologically sub-dominant region. Methods: Two household studies were conducted in Managua, Nicaragua. Household contacts were tested for influenza using RT-PCR. We compared pre-existing antibody levels against full-length hemagglutinin (FLHA), HA stalk, and neuraminidase (NA) measured by ELISA, along with initial HA inhibition assay (HAI) titers, between infected and uninfected participants. Results: A total of 899 individuals participated in household activation during three A/H3N2 seasons with 329 infections occurring. A four-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (OR=0.82, 95%CI 0.68-0.98, p=0.04). In 0-14-year-olds, anti-NA antibodies (OR=0.67, 95%CI 0.53-0.85, p<0.01) were associated with protection, but anti-HA stalk antibodies were not. In adults, anti-HA stalk antibodies were independently associated with protection (OR=0.72, 95%CI 0.54-0.95,p=0.02). Conclusions: The HA stalk is an independent correlate of protection against A/H3N2 infection, though this protection is age dependent. This supports the continued exploration of the HA stalk as a target for broadly protective influenza vaccines and suggests that the protective benefits may depend on age and influenza exposure history.

Background Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically subdominant region, has not been established for influenza virus A/H3N2. Methods Household transmission studies were conducted in Managua, Nicaragua, across 3 influenza seasons. Household contacts were tested for influenza virus infection using reverse-transcription polymerase chain reaction. We compared preexisting antibody levels against full-length HA, HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay, along with hemagglutination inhibition assay titers, between infected and uninfected participants. Results A total of 899 individuals participated in household activation, with 329 infections occurring. A 4-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (adjusted odds ratio [aOR], 0.82 [95% confidence interval {CI}, .68-.98]; P = .04). In adults, anti-HA stalk antibodies were independently associated with protection (aOR, 0.72 [95% CI, .54-.95]; P = .02). However, in 0- to 14-year-olds, anti-NA antibodies (aOR, 0.67 [95% CI, .53-.85]; P < .01) were associated with protection against infection, but anti-HA stalk antibodies were not. Conclusions The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history.

Abstract Background Children constitute an important component of the influenza burden and community transmission, but the frequency of asymptomatic infection and post-influenza sequelae at the community level is poorly understood. Methods Two community-based prospective cohort studies (2011–2020, 2017–2020) and 1 case-ascertained study (2012–2017) were conducted in Managua, Nicaragua. Non-immunocompromised children aged 0–14 years with ≥1 influenza infections, determined by polymerase chain reaction and hemagglutination inhibition assay, were included. Results A total of 1272 influenza infections occurred in the household-based portion of the study. Influenza infection was asymptomatic in 84 (6.6%) infections, and the asymptomatic fraction increased with age (1.7%, 3.5%, and 9.1% for ages 0–1, 2–4, and 5–14, respectively; P < .001). Of asymptomatic children, 43 (51.2%) shed virus, compared to 1099 (92.5%) symptomatic children (P < .001). Also, 2140 cases of influenza occurred in the primary care portion of the study. Sequelae of influenza were rare, with the most common being pneumonia (52, 2.4%) and acute otitis media (71, 3.3%). A/H1N1 had higher age-adjusted odds of acute otitis media (odds ratio [OR] 1.99, 95% confidence interval [CI]: 1.14–3.48; P = .015) and hospitalization (OR 3.73, 95% CI: 1.68–8.67; P = .002) than A/H3N2. B/Victoria had higher age-adjusted odds of pneumonia (OR 10.99, 95% CI: 1.34–90.28; P = .026) than B/Yamagata. Conclusions Asymptomatic influenza infection is much less common in children than adults, although viral shedding still occurs in asymptomatic children. Post-influenza sequelae are rare in children in the community setting, and virus strain may be important in understanding the risk of sequelae.

The present study was undertaken to investigate the role of spinal somatostatin SSTR2A receptors in nociceptive processing. SSTR2A receptor-like immunoreactivity was found in a dense network in the spinal cord of normal rats. With Western blot analysis a major band of approximately 80–85 kDa was detected. Both immunohistochemistry and immunoblot analysis indicated a significant increase in SSTR2A receptor content in the spinal cord 6 h after noxious thermal stimulation that lasted for at least 24 h. However, there were no notable changes in SSTR2A receptor content 3, 6, 12, or 24 h after noxious mechanical stimulation. Effects of intrathecally administered polyclonal antiserum to SSTR2A receptor (anti-SSTR2A) on thermal and mechanical pain thresholds were determined with behavioral tests. In normal rats, pretreatment with anti-SSTR2A (1 μl, intrathecal) did not affect paw withdrawal latency or pinch threshold. Hindpaw inflammation induced by complete Freund's adjuvant led to thermal and mechanical hyperalgesia as reflected by a robust decrease in paw withdrawal latency and pinch threshold. Significant attenuation of the thermal hyperalgesia was observed 3, 5, 7, 9, and 24 h after pretreatment with anti-SSTR2A. This effect disappeared in another 24 h. In contrast, pretreatment with anti-SSTR2A failed to exert any notable effect on adjuvant-induced mechanical hyperalgesia. The present findings provide the first evidence that SSTR2A receptors are responsible for thermal, but not mechanical, nociceptive transmission in the spinal cord. The results also suggest that somatostatin has an excitatory role in spinal nociceptive processing and that there are differential receptor responses to different types of noxious stimuli.

Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults (n = 4478) experience boosting and waning of antibodies during and after major Zika and dengue epidemics. We develop a susceptible-infected-recovered-susceptible (SIRS-type) model that tracks immunity by titer rather than number of infections to show that boosts in highly immune individuals can contribute to herd immunity, delaying their susceptibility to transmissible infection. In contrast, our model of lifelong immunity in highly immune individuals, as previously assumed, results in complete disease eradication after introduction. Periodic epidemics under this scenario can only be sustained with a constant influx of infected individuals into the population or a high basic reproductive number. We also find that Zika virus infection can boost DENV immunity and produce delays and then surges in dengue epidemics, as observed with real epidemiological data. This work provides insight into factors shaping periodicity in dengue incidence and may inform vaccine efforts to maintain population immunity.

ABSTRACTBackgroundChildren 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.MethodsTo 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 RT-PCR. Wavelet analyses were used to examine seasonality. Generalized growth models (GGMs) were used to estimate effective reproduction numbers.ResultsFrom 2011-2019, 3,016 children participated, with an average of ∼1,800 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%CI: 13.9-15.1) and 1.0 influenza-associated ALRI case (95%CI: 0.8-1.1). 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.ConclusionsThis 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.SummaryIn this long-running influenza cohort, we found a substantial incidence of RT-PCR-confirmed influenza, and report by subtype/lineage. Infants born during influenza epidemics were protected from infection that first year. The mean effective reproduction number across years was 1.2.