Journal of the Pediatric Infectious Diseases Society

Importance: Understanding population differences in epidemiology, clinical presentation, and genetic architecture remains a major challenge for all rare genetic disorders. Hirschsprung disease (HSCR), despite being the commonest cause of neonatal intestinal obstruction, has been poorly studied with respect to its significant heterogeneity across U.S. populations. Objective: To characterize self-identified race and ethnicity differences in HSCR incidence, clinical presentation, and genetic architecture in the United States from diverse data sources. Design, Setting, and Participants: We used retrospective, population-based surveillance data from 3 independent US wide sources - (1) The National Birth Defects Prevention Network (NBDPN; 1996-2010), (2) aggregated electronic health record data from Epic COSMOS (1997-2025), and (3) individual level clinical and genomic data from the Hirschsprung Disease Research Collaborative (HDRC; 2011-2025). Statistical analyses of incident HSCR cases identified at birth, across time and geography, in conjunction with clinical phenotypes and genome sequences from unrelated HDRC probands were performed to characterize epidemiologic, phenotypic and genetic heterogeneity in HSCR. Exposures: HSCR cases were identified based on standardized clinical diagnostic criteria, primarily rectal biopsy with histopathologic confirmation of aganglionosis. The disease was defined using ICD-9-CM code 751.3, CDC/BPA code 751.30-751.34. and ICD-10-CM code Q43.1. Patients were classified by self-identified race and ethnicity (SIRE), with primary comparisons conducted between non-Hispanic Blacks/African Americans (Blacks) and non-Hispanic Whites (Whites). Main Outcomes and Measures: HSCR incidence and the frequency of clinical features were estimated overall and by SIRE. We also estimated the individual and total genetic burden of rare pathogenic coding variants and common noncoding regulatory variants at established HSCR genes by population. Results: Overall HSCR incidence in the U.S. was 2.04 per 10,000 live births (95% CI, 1.99-2.09) as previously estimated. We show, Blacks have the highest HSCR incidence (2.83-3.13 per 10 000 live births), in comparison to Whites (1.89-2.02) and Asians (1.54-1.98), a difference not previously ascertained from previous smaller cohorts from limited geographical regions. This difference persists across surveillance times and geography. This incidence difference from NBDPN is consistent with Epic COSMOS, a nation-wide, independent hospital-based data source. Clinically, Blacks are more likely to present with isolated HSCR and with milder manifestations at birth, including chronic severe constipation (CSC). Genetically, the burden of pathogenic coding variants did not differ between Blacks and Whites. However, Blacks had a significantly higher enrichment of two non-coding regulatory variants (rs199582499 and rs28735659) at the SOX10 gene locus, as compared with Whites. Conclusions and Relevance: This study demonstrates, for the first time, that Black HSCR patients in the U.S. have a higher incidence accompanied by milder clinical presentation and distinct noncoding regulatory SOX10 variants as compared to White patients. Nevertheless, Blacks are severely under-represented in U.S. studies of HSCR leading to significant health disparities in their care and management.

As vaccination rates have declined, large measles outbreaks have taken hold in vulnerable populations. In 2025, the United States saw the highest number of measles cases since 1991. After Utahs first case in June 2025, the Utah Public Health Laboratory (UPHL) began performing whole genome sequencing (WGS) on clinical measles samples. As Utahs outbreak grew, public health professionals used WGS data to identify clusters of disease, and combined genomic and epidemiologic data to identify factors that may fuel the spread of disease throughout the state. This study used sequenced samples from 65% of reported measles cases in Utah. Time-scaled and maximum likelihood phylogenetic trees were generated. A single nucleotide polymorphism (SNP) threshold of one was used to generate genomic clusters, and a Fishers Exact test was used to determine association between genomic cluster and epidemiological variables. Epidemiological clusters were assessed using annotated phylogenetic trees. We found multiple introductions of measles into Utah, with one accounting for the majority of cases. As measles spread, two phylogenetic clades emerged with differing geographical case compositions. We identified a significant association between shared school and genomic clustering, and we reconstructed transmission chains within schools and emerging from school sporting events. This study demonstrates the utility of WGS in real-time outbreak investigations. Sequencing data allowed for gaps in epidemiological data to be filled, revealing undetected transmission and clarifying whether cases belong to a known outbreak. We also highlight that schools and high-contact sporting events played a significant role in fueling transmission across the state.

Background: Pertussis has resurged in the post-COVID-19 era, yet diagnostic delay remains a barrier to timely treatment and transmission interruption, particularly among adults. Methods: Retrospective observational cohort study of 787 patients with confirmed pertussis from January 2016 through March 2026 across two South Carolina health systems. Electronic health record data from the 60 days preceding confirmation were used to characterize diagnostic timing (same-day vs. delayed), delay duration, and respiratory pathogen testing patterns including pertussis test modality. Results: Adults accounted for 48.4% of cases (median age 16 years [IQR 4-52]; 61.6% female). Same-day diagnosis was highest among children aged 1-4 years (75.4%) and lowest among adults aged 50 and older (approximately 50%). Among the 305 patients (38.8%) with delayed diagnosis, median delay ranged from 7-12 days in children to 22.5-26.5 days in adults aged 50 and older. Delay did not vary significantly by COVID-19 period, race, ethnicity, or insurance type. Testing breadth was greater in inpatient and emergency settings than outpatient. Pertussis testing was predominantly PCR-based in children but serologic in adults, potentially reflecting later clinical presentation relative to illness onset; however, the near-absence of PCR testing in older adults may contribute to missed diagnoses during the early illness window when PCR sensitivity is highest. Conclusions: Older adults experienced markedly delayed pertussis diagnoses compared with children. Earlier consideration of pertussis in adults with prolonged cough, including PCR testing early in illness before serologic conversion, may reduce diagnostic delay and facilitate timelier treatment and contact tracing.

Importance Age based screening and prevention guidelines in healthcare are developed largely in populations without Down syndrome (DS). If disease risk among individuals with DS differs significantly relative to typically developing (TD) individuals of similar ages, standard guidelines may overlook critical windows of care. Objective To determine the age specific risk of ten common conditions in individuals with DS compared to a matched TD cohort to evaluate the presence of risk modification by age. Design Retrospective longitudinal cohort study. Setting Midwest healthcare system. Participants 4,912 individuals with DS and 37,924 TD controls, with clinical encounters between January 2005 and May 2025. Total person years (PYs) were 25,896 and 149,078 respectively. Exposure DS status Main Outcomes and Measures Incidence of acute sinusitis, anxiety, asthma, depression, gastroesophageal reflux disorder, nervous system disorders, respiratory failure, thyroid gland disorders, vasomotor/allergic rhinitis, and vitamin D deficiency. Incidence rate ratios (IRR) trajectories were analyzed using generalized additive mixed models. Wald tests assessed the presence of age modification. Results In our DS cohort (median age 24, 48% female), we found evidence of age-related risk modification in 6 of 10 conditions examined. The relative incidence of anxiety was significantly lower among individuals with DS in early childhood (at age 5, IRR 0.23, 95%CI 0.19, 0.29), compared to TD controls of the same age. However, risk in the DS cohort increased with age approaching equal levels with controls around ages 65. Similar trends were observed for depression. The association between DS and gastroesophageal disease was largely null except between ages 1 to 8, where the incidence among DS cohort was elevated (5 to 7 cases per 1000 PYs) compared to controls (2 to 3 cases per 1000 PYs). The association between DS and respiratory failure was statistically insignificant until age 53 to 70, where incidence among individuals with DS rose sharply (13 to 30 cases per 1000 PYs), while for TD counterparts it remained constant at 8-9 cases per 1000 PYs. Lastly, risk of vitamin D deficiency fluctuated with a peak at age 20 (IRR 2.34, 95%CI 2.02, 2.72). Conclusions and Relevance These findings demonstrate age effect modification among individuals with DS across a variety of disease conditions and highlight the importance of population-specific care guidelines.

Importance: Maternal vaccination and long-acting monoclonal antibodies are now available in the U.S. to prevent RSV. Long-acting monoclonal antibody administration in the U.S. commonly occurs after hospital discharge in outpatient settings, leaving some infants unprotected early in life when severe RSV risk is highest. Comparative effectiveness between the two interventions and whether delays affect effectiveness estimates have not been quantified. Objective: To evaluate the effectiveness of infant long-acting monoclonal antibody strategies and a maternal vaccination strategy, each compared to no intervention, and the comparative effectiveness of intervention strategies when accounting for real-world delays in monoclonal antibody receipt. Design: Cohort study using target trial emulation to compare four strategies for prevention of RSV-related outcomes. Setting: The U.S. between 2023 and 2025 using a nationwide database of employer-sponsored commercial insurance claims. Participants: 120,586 commercially insured mother-infants, whose infants were born in the U.S. during the 2023-2024 or 2024-2025 RSV season. Infants who could not be paired with their mother's record, did not enroll in commercial insurance within 75 days from birth, received palivizumab, and had an implausible birth date were excluded. Interventions: Comparison of four RSV prevention strategies: (i) maternal RSVpreF; (ii) long-acting monoclonal antibody given within the first week of life (mAb as intended); (iii) long-acting monoclonal antibody given within a six-month grace period from birth (mAb within grace period); and (iv) a control. Main outcomes and measures: Effectiveness against first RSV-associated hospitalization and medically-attended RSV illness was summarized using adjusted hazard ratios (aHR) and estimated using an inverse propensity weighting approach, with weights accounting for maternal age, maternal comorbidities affecting pregnancy, obstetric and newborn complications, season, region, and birth timing relative to October 1. A weighted Kaplan Meier estimator was used to estimate strategy-specific cumulative incidence of RSV outcomes over time. Results: In the first five weeks of life, the mAb within grace period strategy doubled the hazard of RSV hospitalization (aHR: 2.0 [95% CI: 1.0-4.9]) and increased the hazard of medically-attended RSV (aHR: 1.6 [95% CI: 1.0-2.7]) compared to the maternal RSVpreF strategy. The hazard for RSV hospitalization was similar for the mAb as intended strategy compared to the maternal RSVpreF strategy (aHR = 0.9 [95% CI: 0.3-1.9]). Conclusions and relevance: RSVpreF and monoclonal antibodies were similarly effective when monoclonal antibodies were administered close to birth, but when accounting for real-world delays in monoclonal antibody receipt, the maternal RSVpreF strategy was more effective than the mAb within grace period strategy.

Background Shigella is a leading cause of diarrhea in children in low- and middle-income countries (LMICs). Optimizing the impact of vaccines necessitates an accurate characterization of Shigella serotype prevalence. We describe the burden, epidemiology and characteristics of S. sonnei and S. flexneri diarrhea in the Global Pediatric Diarrhea Surveillance (GPDS) network. Methods GPDS is a World Health Organization-coordinated surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years. GPDS enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens from these children were tested by quantitative polymerase chain reaction to detect a broad range of enteropathogens as well as to identify S. sonnei and S. flexneri serotypes. We estimated pathogen-specific attributable fractions and incidence of diarrheal hospitalizations. Results During 2017-2022, GPDS enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. Globally, Shigella caused 9.8% (95% Confidence Interval [CI]: 8.4, 11.3) of hospitalized diarrhea, with 28.3% of cases occurring in children aged {pound}12 months. The estimated attributable incidence of Shigella-associated diarrhea hospitalizations decreased from 1.27 (95% CI: 0.95, 1.64) per 1,000 child years in 2017-2018 to 0.88 (0.67, 1.10) in 2021-2022. Among typeable Shigella cases, 34.8% were S. sonnei, 24.2% were S. flexneri 2a, and 9.9% were S. flexneri 1b. Vaccines currently in development would cover an estimated 59.0% to 72.2% of cases. Conclusions These findings support the role of Shigella as an important cause of the most severe diarrhea in young children. The breadth of homotypic protection provided by Shigella vaccines in clinical development varied by region, and these broadly representative data can aid in prioritization. Non-dysenteric Shigella could not be readily differentiated from other causes of hospitalized diarrhea based on clinical characteristics.

Diarrhea remains a leading cause of child morbidity and mortality. Improved and ongoing estimates of the etiology of hospitalized pediatric diarrhea in low- and middle-income countries (LMICs) are needed to help prioritize and evaluate the use of existing and upcoming vaccines and interventions. The Global Pediatric Diarrhea Surveillance (GPDS) network is a World Health Organization (WHO)-coordinated public health surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years in LMICs. The GPDS network enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs. Randomly selected stool specimens were tested by TaqMan Array Card quantitative reverse-transcription polymerase chain reaction (qPCR) for 16 pathogens associated with diarrhea. We estimated pathogen-specific attributable fractions (AFs) and incidence of diarrheal hospitalizations at the global, regional, and country levels during 3 time periods: 2017-2018, 2019-2020, and 2021-2022, with a focus on the most recent results. During 2017-2022, the GPDS network enrolled 70,750 children aged <5 years hospitalized with diarrhea, of which 16,458 (23.3%) were randomly selected for qPCR testing. The most prevalent pathogen detected, regardless of quantity or modeled etiologic attribution, was rotavirus (weighted prevalence 30.4%), followed by adenovirus 40/41 (19.1%), norovirus (17.9%), Shigella (14.1%), and Campylobacter jejuni/coli (8.6%). Overall, in 2017-2022, rotavirus was the leading etiology globally (AF 32.5%; 95% Confidence Interval (CI): 27.4, 37.6), followed by Shigella (9.8%; 8.4, 11.3), adenovirus 40/41 (8.6%; 6.3, 10.8) and norovirus (6.7%; 5.6, 7.7). Over time, rotavirus consistently declined from an AF of 36.7% (95% CI: 28.7, 46.7) in 2017-2018 to 26.7% (20.7, 34.1) in 2021-2022. Norovirus AF increased slightly from 6.2% (4.7, 7.7) in 2017-2018 to 7.3% (5.0, 9.2) in 2021-2022. Global Shigella burden remained stable, and adenovirus 40/41 demonstrated significant volatility, peaking globally in 2019-2020 (11.9%; 5.9, 17.5). In 2021-2022, rotavirus was the leading cause of hospitalized diarrhea in 6 of 9 geographic groupings, norovirus predominated in Central and South America, and Shigella was the leading etiology in South Asia. In the subset of countries that had introduced rotavirus vaccine, the leading etiologies in 2021-2022 were rotavirus (18.4%; 15.8, 21.5) and Shigella (16.4%; 11.8, 21.1). In 2021-2022, rotavirus had the highest attributable incidence of hospitalized diarrhea in children (2.3 per 1,000 child-years; 1.8, 3.0), followed by Shigella (0.9; 0.7, 1.1), norovirus (0.6; 0.4, 0.8) and adenovirus 40/41 (0.6; 0.4, 0.8). Despite the widespread use of rotavirus vaccines, rotavirus remained the leading cause of severe diarrhea among children aged <5 years in LMICs globally. However, the proportion of pediatric diarrhea attributable to rotavirus consistently declined from 2017-2018 to 2021-2022, and there were notable differences in the distribution of diarrheal etiologies between regions and across time periods. Shigella, norovirus, and enteric adenoviruses were also associated with a substantial burden of disease. Improving the efficacy and coverage of rotavirus vaccination and prioritizing interventions against other enteric pathogens could further reduce diarrhea morbidity and mortality.

Pregnant women with late latent or latent of unknown duration syphilis are recommended to receive three doses of benzathine penicillin G each 9 or fewer days apart; data on interval variations are limited. We found no significant difference in risk of congenital syphilis between 9-day and 6-8 day dosing intervals.

BackgroundCOVID-19 pandemic modified trends of infant bronchiolitis, leading cause of emergency room (ER) attendance in infants in high income countries, primarily due to Respiratory Syncytial Virus. Understanding recent pandemic-related epidemiological shifts could inform affordable prevention efforts to improve sustainability and coverage of prophylactic treatments beyond maternal vaccines and infant monoclonal antibodies. MethodsWe estimated incidence rates (IR) of bronchiolitis ER presentations in 0-6month olds in 2012-2023 in a region-wide cohort of almost 1 million births using administrative health data from Lombardy, Italy. To assess potential contributors, we investigated direct and indirect COVID-19-related factors, including disease severity, shape of the epidemic peak, parental health seeking behaviour and vaccine coverage. We estimated COVID-19 maternal vaccination associations using mothers-infants data linkages and multivariable-adjusted logistic regression. FindingsCompared to pre-pandemic levels, IRs doubled in 2021-2023 (from 2 to [&ge;] 4/100 person-time). The surge could not be explained by changes in infant age at ER visit, clinical severity or in the shape of the epidemic peak. Adjusted models showed little support for a role of infant routine or maternal COVID-19 vaccination on bronchiolitis episodes (respectively hazard ratio 1.09, 95%CI: 0.98-1.22 and odds ratio 0.91, 95%CI: 0.76-1.09). InterpretationThe post-pandemic increase in infant bronchiolitis is likely driven by multiple epidemiological changes rather than a single factor. As maternal RSV vaccination and infant RSV monoclonal antibodies are introduced and scale up, identifying these mechanisms will be critical to maximise their public health impact, inform complementary prevention strategies, and improve preparedness for future RSV epidemics.

Intrauterine infection and inflammation are major causes of preterm labor, yet antibiotics alone often fail to prevent preterm birth despite achieving microbial clearance. Interleukin1 (IL1) is a key mediator of intra-amniotic inflammation and functional progesterone withdrawal, processes linked to labor initiation. We tested whether IL1 blockade with the clinically approved IL1 receptor antagonist, anakinra, could reduce inflammation and preterm labor in a Rhesus macaque model of intra-amniotic Escherichia coli infection followed by delayed antibiotic treatment. Here we show that anakinra reduced the incidence of preterm labor by 40% (p=0.07), attenuated inflammation in the fetal membranes and cervix, and preserved progesterone receptor-B abundance in the fetal membranes. These effects were most pronounced in animals protected from preterm labor. Our findings in a relevant model support the translational potential of combining IL1 blockade with antibiotics for infection-associated preterm labor. One sentence summaryRecombinant human IL1 receptor antagonist (anakinra) decreased E. coli infection induced preterm labor and partially decreased intrauterine inflammation in a non-human primate model of inflammation mediated preterm labor.

Background. Obesity has been associated with higher risk of dengue virus (DENV) infection and disease, yet its influence on antibody responses to DENV remains undefined. Methods. We evaluated whether nutritional status -- based on BMI z-score (BMIz) -- or blood markers of body fat -- leptin and adiponectin --are associated with binding and/or neutralizing antibody responses to DENV in 85 children in the Nicaraguan Pediatric Dengue Cohort Study who experienced a primary DENV infection in 2019. Associations were estimated using linear models adjusting for age, sex, and DENV infection outcome. Results. Compared to children with normal weight, those with obesity had higher quantities of DENV binding antibodies (fold-change [FC] 1.89, 95% confidence interval [CI] 1.02, 3.48) but no difference in neutralizing antibodies. Likewise, leptin concentration was associated with higher quantities of binding antibodies (FC 1.22, 95%CI 1.09, 1.37), while adiponectin was associated with lower quantities (FC 0.79, 95%CI 0.67, 0.94), and neither was associated with neutralizing antibodies. Lower neutralizing efficiency (neutralizing/binding antibodies) was observed in children with obesity (FC 0.67, 95%CI 0.48, 0.93). Conclusions. Our results indicate that obesity is associated with higher antibody quantity (binding) but not higher quality (neutralization) post-primary DENV infection -- implying that antibodies generated by children with obesity have lower neutralization efficiency, requiring greater quantities to reach similar levels of neutralization than children with normal weight. Further, the agreement among the three models using distinct proxies of body fat -- BMIz, leptin, and adiponectin -- demonstrates that adipokines are useful in supplementing BMIz analysis or as independent predictors of immune responses.

BACKGROUND Human cytomegalovirus (HCMV) is the leading global infectious cause of birth defects. Despite its prevalence as a cause of life-long disabilities, there are no licensed vaccines to prevent congenital CMV (cCMV), and correlates of protection remain poorly understood. To address this, we identified humoral immune responses to primary HCMV infection during early pregnancy associated with odds of vertical transmission. METHODS Maternal plasma was collected from a trial that screened >200,000 and enrolled 399 pregnant women serologically diagnosed with primary HCMV infection prior to randomization for hyperimmunoglobulin or placebo therapy (NCT01376778), where 78 transmitted cCMV. Plasma IgG, IgM, and IgA binding to HCMV antigens, neutralization, antibody-dependent cellular phagocytosis, and inhibition of cell-associated viral spread were measured and related to transmission outcome. RESULTS In a case-control conditional logistic regression, IgM binding to HCMV entry glycoproteins was associated with increased odds of cCMV, identifying potential biomarkers of congenital infection. In contrast, IgG binding to UL16, UL141, prefusion-like gB, gB antigenic domains (AD) 4+5, and gH/gL were associated with decreased odds of cCMV. Surprisingly, IgG binding to the immunodominant gB AD-1 region, pp150, and cell-associated gB were associated with increased odds of cCMV. A LASSO regression model selected IgG responses against UL16 and gB AD-4+5 as associated with decreased odds of transmission, suggesting their potential importance as vaccine targets. CONCLUSION UL16 and domain specificity of gB-specific IgG responses differentially impact cCMV odds following acute infection, emphasizing the importance of rational antigen selection and gB conformation for HCMV vaccine design to eliminate cCMV.

Background: The relationship between recent viral infection and subsequent susceptibility to, or protection against, other viruses remains unclear, particularly across ages and symptom status. Methods: A prospective cohort study enrolled participants aged 6 months to 49 years in Washington and Oregon, USA, 2022-2024. Weekly nasal swabs were tested for SARS-CoV-2, respiratory syncytial virus (RSV), and influenza A/B; additional swabs were collected during symptomatic illness and were also tested for parainfluenza (PIV) 1-4, endemic human coronaviruses (hCOV), adenovirus, human metapneumovirus, human rhinovirus (hRV), and enteroviruses. Proportional hazards regression models were used to characterize associations between incident symptomatic infection (illness) and history of recent illness due to other viruses (within 1-7, 8-14, 15-30, 31-60, 61-90, 91-180 days), adjusted for geographic region, age, sex, daycare/school/work attendance, household size, and number of children in the household. For SARS-CoV-2, influenza, and RSV, these analyses were repeated to study incidence of infection (including asymptomatic cases). Findings: Of 3,560 participants, 2,969 (83%) had [&ge;]1 illness over 4,299 person-years. Adjusted hazard ratios (aHRs) in the short term ([&le;]2 weeks) after an illness were predominantly below 1, indicating that recent viral illness was often associated with lower risk of subsequent illness with other viruses. Across age groups, recent hRV illness was associated with lower risk of hCOV, PIV, and RSV illness (aHRs 0.07-0.27). SARS-CoV-2 illness was associated with a higher short-term risk of adenovirus and PIV illness (aHRs 3.20-3.33). In children aged 6 months-4 years, recent influenza illness was associated with higher short-term risk of SARS-CoV-2 illness. Including asymptomatic infections generally attenuated these associations. Interpretation: Some viral illnesses may alter short-term susceptibility to subsequent viral illnesses. Interactions may differ by age and symptom status. Funding: US Centers for Disease Control and Prevention; Washington State Department of Health.

Background: A large increase in mortality from severe acute respiratory infections (SARI) in Brazil in 2025 was mainly driven by influenza A and respiratory syncytial virus (RSV) among children and the aged, but 2026 data remain largely unpublished. Methods: Secondary data on SARI by age group (<2, 2-4, 5-14, 15-49, 50-64, 65+ years) and virus (Influenza A/B, RSV, SARS-CoV-2, adenovirus, rhinovirus, bocavirus, and metapneumovirus) were retrieved for 35 weeks of 2026. Weekly variations in infection rate (IR) and mortality rate (MR) were described by virus and age group. Case fatality ratio (CFR) and vaccine-preventable deaths from influenza, RSV, and SARS-CoV-2 were analysed by age group. Missing virus classification was estimated by multinomial regression. Poisson-based 95% confidence intervals (CI) were calculated for MR. Results: Influenza A infections quintupled during February and March, with a mortality peak in April, mainly due to H2N3. RSV and rhinovirus caused more deaths than influenza viruses, especially among young children (<2) and the aged (65+). The former were most frequently infected by RSV and the latter by rhinovirus. For those 50 years or older, influenza B reached a CFR of about 20%, compared with 5-15% for influenza A, metapneumovirus, rhinovirus, and other non-subtyped viruses. The highest vaccine-preventable MRs per 100,000 were 17.23 for the oldest and 8.62 for the youngest. Under ideal conditions, 6418 lives could have been saved, about half among children and adolescents <15 years old. Conclusions: Vaccine-preventable SARI in Brazil exerted a high toll in fall and winter 2026, mainly due to influenza A, RSV, and rhinovirus. Better vaccine coverage may significantly reduce this toll.

Respiratory syncytial virus infection is a common cause of hospitalizations in infants and elderly patients. With the increased availability of vaccines and therapeutic antibodies, surveilling the sequence landscape of viral genomes is important to increase awareness of potentially neutralizing mutations. During the 2023-24 and 2024-25 RSV seasons, we collected unpaired nasopharyngeal swab specimens from patients presenting to Arizona healthcare systems with symptoms of influenza-like illness. Using either tiled am-plicon-based enrichment or a commercial oligo hybrid-enrichment panel and next generation sequencing, we obtained genome sequences for RSV and co-infecting viruses. We performed phylogenetic and genomic analyses to classify RSV genomes and detect mutations in the antigenic sites of the F protein and conserved central domain of the G protein. Phylogenetic analysis showed RSV-A strains belonged to the A.D. 1, A.D.2, A.D.3, and A.D. 5 subclades. RSV-B genomes belonged to the B.D.4.1, B.D.4.1.1, B.D.E.1, B.D.E.5, and B.D.E. 7 clades. We found 9 polymorphic sites located in the antigenic sites of the F protein in our RSV-A genomes and 18 polymorphic sites in our RSV-B genomes over the two-season surveillance period. We identified 7 polymorphic sites in our RSV-A genomes and 8 polymorphic sites in our RSV-B genomes that are in the conserved central domain of the G protein. We also discovered 3 (6.7%) and 27 (15.8%) incidences of viral coinfections in the 2023-24 and 2024-25 seasons, respectively. Viral genomic surveil-lance plays an important role in maintaining the efficacy of vaccine and therapeutic agents. Continued monitoring of circulating variants is an important component of public health.

Background: Mortality and hospital admissions due to Severe Acute Respiratory Infection (SARI) peaked between January and August 2025 in Brazil. Methods: The Brazilian Ministry of Health data on hospital admissions and deaths caused by SARI were compiled by age group (<5, 5-14, 15-49, 50-64, 65+ years) and quarter between January 2023 and June 2025. SARI causes were aggregated into SARS-Cov-2, Influenza, Respiratory Syncytial Virus (RSV), and other viruses (parainfluenza, adenovirus, rhinovirus, bocavirus, metapneumovirus). Multinomial regression was used to impute likely causes of death when these were not laboratory confirmed. Results: In the second quarter of 2025 (2025/2), RSV mortality rate among children <5 years reached 60 per 100,000, which is a 43% increase compared with 2024/2. Mortality rate for the joint impact of parainfluenza, adenovirus, rhinovirus, bocavirus, and metapneumovirus in the same age group doubled from 20 to 40 on the same scale in 2025/2 compared to 2024/2. Over the same period, influenza mortality tripled among the aged, whereas mortality due to other respiratory viruses increased less dramatically, except for SARS-CoV-2, which decreased among the aged from 150 to 25 per 100,000 between 2023/1 and 2025/2. Other age groups remained relatively stable over the period. The variation in hospital admissions largely followed that of mortality. Conclusions: While deaths and hospital admissions caused by SARS-CoV-2 declined rapidly since 2023, mortality rates of other respiratory viruses, mainly influenza and RSV, increased significantly among children <5 years and the aged in 2025/2. Public health policies that facilitate vaccine uptake against these infections should be given high priority.

The longitudinal effects of initial influenza exposure on the magnitude, persistence, and antigen specificity of antibody responses during infancy remain incompletely understood. We investigated humoral antibody responses following primary influenza infection or seasonal vaccination in a prospective US birth cohort with weekly respiratory surveillance for influenza infection. Influenza-specific serum IgG binding to H1 and H3 haemagglutinin (HA) antigens, HA inhibition (HAI), and live-virus neutralizing antibody responses were assessed longitudinally. To minimize influence of maternally derived antibodies, analyses of primary exposure responses were restricted to infants for whom influenza-specific maternal antibodies had declined below the assay detection limit before exposure. Antibody responses were compared following primary infection and vaccination and examined after subsequent annual vaccination. We found that maternal influenza-specific IgG declined rapidly during early infancy. Among infants without detectable pre-exposure influenza-specific antibodies, primary influenza infection was associated with greater post-exposure antibody responses and less measurable decline over follow-up than primary vaccination. These groups differed in age, calendar season, and exposure characteristics, limiting direct attribution of these differences to route of exposure. In infants with previous influenza infection followed by vaccination, responses after subsequent vaccination initially showed greater binding to the previously infecting subtype among the tested HA antigens. With repeated vaccination, responses became more distributed across the tested antigens. Our findings reveal differences in the magnitude, persistence, and antigen specificity of antibody responses according to the nature and sequence of influenza exposure. By prospectively capturing early-life exposures, this study provides longitudinal evidence linking exposure history to subsequent humoral antibody responses.

Spontaneous preterm birth (sPTB) affects ~9.9% of pregnancies worldwide and is driven in part by placental dysfunction, yet the signalling events linking placental dysregulation to spontaneous prematurity remain incompletely defined. Using a cross-sectional design, we profiled 70 placentae from spontaneous term and preterm birth delivery to construct protein co-expression networks and identified 13 hub proteins associated with sPTB. Quantification of placental circulatory proteins in an independent nested case-control set of 53 maternal plasma samples highlighted elevated levels of the transcription factor ladybird homeobox protein 1 (LBX1) in maternal circulation from sPTB cases. Elevated LBX1 in trophoblast cells undergo KPNB1 mediated nuclear import, where it deregulates ribosomal biogenesis and perturbs subsequent ribosomal protein homeostasis, contributing to the accumulation of newly synthesised proteins. Accumulation of these nascent proteins triggers unfolded protein response which may lead to adverse pregnancy outcome. These findings implicate LBX1-mediated ribosomal disruption and activation of unfolded protein response in trophoblasts as a placental mechanism contributing to sPTB.

BackgroundPost-acute COVID-19 syndrome (PACS) can cause persistent disability involving fatigue, post-exertional malaise, neurocognitive symptoms, and autonomic manifestations. A clinically overlapping condition has been reported following COVID-19 vaccination and termed post-acute COVID-19 vaccination syndrome (PACVS), but its underlying mechanisms remain poorly understood. We investigated whether immune dysregulation, autoreactivity, antigen persistence, and viral reactivation--mechanisms implicated in PACS--are also present in PACVS. MethodsThis cross-sectional study included 28 PACS patients, 29 PACVS patients, and 16 convalescent controls (CCG). Clinical manifestations were assessed using ME/CFS-related symptom questionnaires and the Bell Score. T-cell phenotypes and T cells reactive to SARS-CoV-2 Spike, {beta}1/{beta}2-adrenergic receptor, and M3/M4 muscarinic receptor antigens were analyzed by multicolor flow cytometry. Circulating Spike protein and GPCR autoantibodies were quantified by ELISA, and EBV load by qPCR. ResultsPACS and PACVS showed substantial clinical overlap, although several symptoms were more severe in PACS. GPCR autoantibody profiles were comparable between patient groups, while {beta}2-adrenergic receptor autoantibodies were increased compared with CCG. Only three of 57 conventional immunophenotyping parameters differed between PACS and PACVS in unadjusted analyses, whereas both groups showed multiple alterations compared with CCG. Circulating Spike protein was detected in both patient groups, with the highest prevalence in PACVS. {beta}1/{beta}2- and M3/M4-reactive CD4+ T cells were increased, whereas Spike-specific CD4+ T cells were reduced compared with CCG. EBV reactivation was rare. ConclusionsPACS and PACVS exhibit substantial clinical and immunological overlap, including GPCR-directed autoreactivity and altered receptor-reactive T-cell responses. These shared immune-mediated features suggest overlapping pathophysiological mechanisms and warrant investigation of whether therapeutic strategies currently explored for PACS may also be relevant to PACVS.

Streptococcus agalactiae (Group B Streptococcus, GBS) is a Gram-positive opportunistic pathogen and the leading cause of neonatal bacterial meningitis, a life-threatening infection of the central nervous system (CNS) that occurs when bacteria cross the blood-brain barrier (BBB). GBS commonly colonizes the maternal genital tract and is a major cause of invasive neonatal disease, including bacteremia and meningitis. Despite treatment advances, GBS meningitis remains associated with substantial mortality and long-term neurological sequelae. The BBB is a highly specialized barrier formed by brain endothelial cells (BECs) that restrict microbial entry into the CNS through tightly regulated intercellular junctions. The BBB exists within the neurovascular unit, where neurons and other CNS cell types actively regulate endothelial barrier properties through intercellular signaling. However, the contribution of neuronal-endothelial interactions to BBB function during neonatal meningitis remains poorly understood. To investigate the mechanisms by which GBS disrupts and penetrates the BBB, we utilized induced pluripotent stem cell (iPSC)-derived brain-like endothelial cells. EZ-Sphere-derived neurons generated from the same iPSC source were incorporated into an isogenic BBB model to determine whether neuronal-endothelial communication influences GBS interaction with BECs. Neuronal co-culture significantly reduced GBS adherence to and invasion of BECs while preserving tight junction integrity during infection. Application of neuron-conditioned medium similarly decreased bacterial adherence and invasion, suggesting that neuron-derived soluble factors enhance barrier integrity during GBS infection. Together, these findings demonstrate that neuronal signaling enhances BBB resistance to GBS and highlight a previously underappreciated role for neurovascular crosstalk in limiting bacterial pathogenesis. ImportanceGroup B Streptococcus (GBS) is the leading cause of bacterial meningitis in newborns. GBS interacts with and crosses the blood-brain barrier (BBB) contributing to a potentially fatal infection without treatment. Understanding how the BBB interacts with bacterial pathogens is critical for developing new strategies to protect vulnerable infants. In this study, we used human stem cell-derived models to recapitulate the BBB and examine how communication between brain endothelial cells and neurons influence host response to bacterial infection. These findings identify neuronal-endothelial communication as a potential contributor to BBB protection and provide a foundation for future studies aimed at preventing GBS invasion of the central nervous system.