Journal of the Pediatric Infectious Diseases Society

Infectious gastroenteritis (IGE) is a major cause of pediatric morbidity globally, with viral pathogens accounting for a substantial proportion of cases. While seasonal patterns of viral IGE are well recognized, the association between specific environmental exposures, such as ambient temperature, and viral IGE has not been fully quantified. First, we performed a secondary analysis of data from a prospective, multisite study of children presenting to emergency departments at five medical centers across the continental United States, linking individual level laboratory data to environmental exposures, including temperature, humidity, and air pollutants, measured during the 14 days preceding symptom onset. Mixed-effects logistic regression was applied to evaluate the association between viral IGE and environmental exposures, adjusting for site-level clustering and patient age. Among 868 children with IGE, higher ambient temperature was inversely associated with viral etiology (OR 0.50, 95% CI 0.36-0.68, p < 0.001). We did not find statistically significant associations between other environmental variables and viral IGE. Then, to contextualize these individual-level findings in children, we examined all-ages population-level surveillance data from GermWatch, a regional laboratory testing-based infectious disease surveillance system, which demonstrated concordant declines in viral pathogen detection with increasing temperature. These findings support the association of weather with viral transmission patterns. Incorporating environmental context into clinical decision-making may improve diagnostic stewardship and support more effective resource allocation during periods of increased viral IGE prevalence.

Importance: Respiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season. Objectives: To describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups. Design, Setting, and Participants: Surveillance registry of children 8- <24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV). Exposure: Preexisting health conditions potentially increasing risk of severe RSV disease. Main Outcomes and Measures: Patients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared. Results: Among 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001). Conclusions and Relevance: Approximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.

Objective: Lyme disease diagnosis in children is challenging due to atypical presentations and testing limitations. We sought to evaluate the association between Lyme disease and socio-geographic risk factors in children. Materials and methods: We enrolled children undergoing evaluation for acute Lyme disease at one of eight Pedi Lyme Net pediatric emergency departments located in high Lyme disease incidence states over a ten-year period (2015-2024). We defined a case of Lyme disease with an erythema migrans (EM) lesion or a positive two-tier serology result in a child with signs and/or symptoms of acute disease. We linked each childs primary residential county to the following factors: urban-rural residence, socioeconomic status, population-level disease incidence, wildland-urban interface, and "Lyme disease" Google searches. We performed a multi-level logistic regression analysis to evaluate associations between Lyme disease and county factors after adjusting for individual demographics. Results: Among 5,529 children enrolled, 1,396 (25.2%) had Lyme disease: 101 (7.2%) with early-localized disease, 584 (41.8%) with early-disseminated disease, and 711 (50.9%) with late-disseminated disease. Rural residence (aOR 1.9, 95% CI 1.3-2.9), higher socioeconomic advantage (aOR 1.3, 95% CI 1.1-1.4), more "Lyme disease" Google searches (aOR 1.1, 95% CI 1.0-1.2), and higher wildland urban interface (aOR 1.2, 95% CI: 1.0-1.4) were independently associated with Lyme disease. Conclusion: Incorporating socio-geographic factors alongside clinical data may augment diagnostic risk assessment in children with suspected Lyme disease. However, these factors should be incorporated carefully to ensure clinical assessments are not based on a childs geographic location alone.

Zika virus (ZIKV) emerged in Brazil in 2015, causing an unprecedented epidemic of Congenital Zika Syndrome (CZS). A decade later, longitudinal analyses evaluating temporal trends and subnational heterogeneity in CZS burden remain limited. Using publicly available data from SINAN/DATASUS and the RESP-Microcephaly registry (SVS/Ministry of Health, updated July 2024), we conducted a descriptive ecological analysis of ZIKV infection and CZS in Brazil from 2015 to 2023. Of 331,309 notified Zika cases (2015-2023), 213,350 occurred in 2016, followed by an 91.75% decline in 2017 and sustained low-level endemic circulation thereafter. Among 3,751 confirmed microcephaly cases, 1,828 were confirmed with ZIKV etiology. The Northeast region accounted for 75.4% of confirmed cases despite representing approximately 27% of the national population. State-level analyses revealed distinct epidemiological patterns, including persistent microcephaly notifications of non-Zika etiology in Minas Gerais and continued detection of ZIKV-attributed CZS in Amazonas and Goias through 2023. These findings highlight pronounced geographic disparities in congenital Zika burden, reflect significant heterogeneity in diagnostic capacity, and underscore the need for sustained surveillance and systematic etiological investigation of congenital abnormalities in the post-epidemic era.

Background: Diarrheal illness in children leads to 3.5 million care visits and 200,000 hospitalizations annually in the US. Viruses are responsible for most pediatric diarrheal cases, yet limited guidance on distinguishing viral from bacterial etiologies complicates clinical decision-making, especially regarding empiric antibiotic use. Methods: We used clinical and qualitative molecular etiologic data from the Implementation of Molecular Diagnostics for Pediatric Acute Gastroenteritis (IMPACT) study to develop prediction models for viral etiology of diarrhea. We used conditional random forests to identify informative clinical and environmental predictors and evaluated model performance using logistic regression and random forests within a 5-fold cross-validation framework. We conducted external validation using the Alberta Provincial Pediatric Enteric Infection Team (APPETITE) dataset. Results: Variables predictive of viral etiology included younger age, non-bloody diarrhea, winter season, and presence of vomiting. External validation showed that an AUC of 0.82 can be achieved with a parsimonious 5-variable model, yielding a sensitivity of 0.92 and specificity of 0.55 Conclusion: Our results suggest that in North American healthcare settings, clinical prediction models can inform decision-making by identifying children with a high probability of viral diarrhea, improving diagnostic clarity, and reducing unnecessary testing and treatment.

The evolving epidemiology of COVID-19, driven by successive SARS-CoV-2 variants of concern (VOCs), has prompted ongoing evaluation of their impact on disease severity in children. In low- and middle-income countries (LMICs), children experience a higher burden of severe respiratory illness and pneumonia-related mortality due to factors such as malnutrition, incomplete immunisation, HIV exposure or infection, tuberculosis, and disparities in access to healthcare services. Hospital-based paediatric studies from LMICs are therefore needed to understand how the epidemiology and severity of COVID-19 have changed across pandemic waves. This study examined 354 hospitalised children with SARS-CoV-2 infection during the ancestral, pre-Omicron (Beta and Delta), and Omicron waves at Tygerberg Hospital in Cape Town, South Africa. We analysed data collected over an extended period, from March 2020 to June 2022. Statistical analyses were used to describe clinical characteristics across variant periods, and multivariable logistic regression models were applied to evaluate associations between potential risk factors and disease severity. Paediatric COVID-19 severity varied across VOC periods, with the highest burden observed during the pre-Omicron (Beta and Delta) waves. In multivariable analyses, younger age and circulating variants were associated with disease severity; CRP levels emerged as a marker associated with more severe illness, and corticosteroid treatment, while also associated with disease severity, reflects clinical response to more severe cases. These findings contribute to a better understanding of the epidemiology and clinical impact of COVID-19 in children and highlight the importance of context-specific surveillance and treatment strategies in resource-limited settings.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition associated with pediatric SARS-CoV-2 infection. While COVID-19 vaccines prevent infection and reduce severity, less conclusive evidence exists regarding their role in preventing MIS-C during breakthrough infections. This systematic review assessed the impact of SARS-CoV-2 vaccination on MIS-C risk during breakthrough infection. Cross-sectional studies, surveillance studies, and cohort studies were included. Of the 944 studies identified, 6 were included. A significant protective effect was seen in patients who received two doses of SARS-CoV-2 vaccination after exclusion of a biased sample (d= 0.71 [95% CI 0.07 to 1.35; p=0.03]). A trend towards a protective effect was seen after one dose of vaccination, but this effect was not statistically significant. Current literature supports a protective effect of two doses of SARS-CoV-2 vaccination against development of MIS-C in breakthrough COVID-19. The evidence supports clinician advocacy for continued vaccination of children against SARS-CoV-2.

Background Neural tube defects (NTDs) are preventable congenital malformations that disproportionately affect low and middle income countries and contribute to disability and mortality. Evidence on the long-term outcomes of children and adolescents with NTDs in Eastern Africa has not been comprehensively synthesised. We conducted a systematic review and meta-analysis to assess survival, complications, and functional outcomes among children with NTDs in this region. Methods We searched PubMed, MEDLINE (Ovid), Cochrane Library, Web of Science, and Africa Index Medicus from the earliest records to April 2025. Two reviewers independently screened studies, assessed quality, and extracted data. We included studies reporting outcomes beyond one year of age, except mortality, which was assessed from birth onwards. Random-effects meta-analyses were undertaken when at least two sufficiently studies were available; otherwise, findings were synthesised narratively. Results Of 597 articles screened, 16 studies involving 2,340 children with NTDs met the inclusion criteria. Pooled cumulative mortality was 23% (95% CI: 12 - 36%) in the neonatal period, 9% (95% CI: 2 - 33%) during infancy, 22% (95% CI: 16 - 28%) in toddlers, 37% (95% CI: 30 - 44%) in pre school aged children and 45% (95% CI: 36 - 54%) in school-aged children. The pooled prevalence of hydrocephalus was 41% (95% CI: 34 - 48%) with little variation by age. Neurogenic bladder increased from 53% (95% CI 49 - 81%) in toddlers to 83% (95 % CI 72 - 91%) in adolescents, while impaired mobility affected about 61% (95% CI 48 - 72%) of adolescents. School enrolment was 53% (95% CI: 39 - 67%), with 9% (95% CI: 4% - 19%) in specialized education. Speech, hearing, and bowel dysfunction were understudied (< 2 studies each). Conclusion Many children with NTDs in the Eastern African region survive beyond infancy but frequently experience hydrocephalus, neurogenic bladder and motor impairment. Longitudinal studies, context-specific guidelines, and follow-up systems are urgently needed to improve care and long-term outcomes.

In newborns seen a median of 11 days after birth, 97/1699 (5.7%) had conjunctivitis, including 13/97 (13.4%) with Chlamydia trachomatis or Neisseria gonorrhoeae detected. Among all babies, we estimated that 6.6% (95% confidence interval 3.8-9.9%) would have C. trachomatis or N. gonorrhoeae detected, of which 87.0% (74.8-93.8%) would be asymptomatic.

Enteric pathogen infections are a major global health challenge, influenced by a variety of host and environmental factors, and their clinical presentation and treatment can be complicated by the presence of co-infections. The prevalence of enteric infections and co-infections tend to vary between rural and urban contexts, likely driven by underlying environmental, geographic, and demographic characteristics. To improve understanding of urbanicity and age on enteric pathogen prevalence and on co-infection risk, we measured 22 enteric pathogens in fecal samples collected from children aged 6, 12, and 18 months across a rural-urban gradient within the ECoMiD birth cohort study (n=473). Enteric pathogen burden was high and increased with age, with at least one pathogen detected in 91% of children at 6 months, 97% at 12 months, and 98% at 18 months. However, prevalence of some pathogens-- notably Salmonella enterica, enterovirus, and rotavirus-- decreased with age. Co-infections were also common (88%), and children were infected with as many as 11 pathogens simultaneously. The most frequently observed co-infection profiles included enteroaggregative E. coli and atypical enteropathogenic E. coli, followed by combinations with diffusely adherent E. coli, enterovirus, enterotoxigenic E. coli, and/or adenovirus. Enteric pathogen detection generally was higher in more rural settings, though patterns varied by pathogen. These results provide useful information for future examination of pathogen dynamics of co-occurrence. Given the ubiquity of enteric infections in high transmission settings, strategies that aim to reduce overall microbial exposure may be needed to supplement interventions targeting control of individual pathogens.

BackgroundFrequent enteric infections can damage the small intestine causing inflammation and malabsorption, leading to environmental enteric dysfunction. We aimed to characterize the association between intestinal inflammation and enteric pathogens among children in low- and middle-income countries (LMICs) who presented to care with diarrhea. Methodology/Principle FindingsWe conducted a cross-sectional analysis within the Enterics for Global Health - Shigella Surveillance Study at six LMIC sites: Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia. From August 2022 to July 2024, rectal swabs and whole stool samples were collected from 4,903 children with medically attended diarrhea aged 6-35 months (44.4% females, n=2178/4903; mean age: 15.4 months {+/-} 7.4 months) and were analyzed for Shigella and four fecal inflammatory biomarkers: hemoglobin, lipocalin-2, myeloperoxidase, and calprotectin via Enzyme Linked Immunosorbent Assays. Caregivers and clinicians demonstrated moderate accuracy in identifying blood in stool compared to fecal hemoglobin (area under the curve (AUC)=0.70). Among 10 pathogens evaluated, Shigella-attributable diarrhea had the highest concentrations of calprotectin, hemoglobin, and myeloperoxidase. Shigella culture-/PCR+ episodes had intermediate levels of inflammation between culture-/PCR- and culture+ episodes. In multivariable models restricted to Shigella episodes, dysentery was positively associated and vomiting was negatively associated with biomarker concentrations, with the strongest associations observed for hemoglobin (dysentery geometric mean ratio: 14.91 g/g (95% CI: 8.77, 25.36) and vomiting geometric mean ratio: 0.44 g/g (95% CI: 0.24, 0.81)). Age, sex, and both acute and chronic malnutrition were not associated with inflammatory biomarker concentrations. Conclusions/SignificanceHemoglobin appeared to be a more sensitive marker of blood in stool than visual observation. While Shigella was associated with heightened levels of all inflammatory biomarkers, hemoglobin was most strongly associated with Shigella, especially among attributable and culture positive episodes. The distinct clinical characteristics of Shigella were most closely associated with elevated hemoglobin concentrations, suggesting its potential utility as a point-of-care diagnostic. AUTHOR SUMMARYDiarrhea is common among children under five years of age in low- and middle-income countries (LMICs). Repeated diarrheal illnesses can damage the gut, leading to issues with growth and brain development. We examined fecal samples collected from 4,903 children with diarrhea who were enrolled in the Enterics for Global Health - Shigella Surveillance Study. We tested samples for diarrheal pathogens and measured four inflammatory biomarkers. We found that hemoglobin better identified blood in stool than visual observation of blood. Additionally, certain biomarkers (calprotectin, myeloperoxidase, and most notably hemoglobin) were higher when diarrhea was caused by bacteria such as Shigella than when diarrhea was caused by viruses. Also, we discovered that Shigella episodes identified using molecular diagnostics caused a similar illness as those identified by culture. These results support that Shigella diarrhea episodes identified by molecular diagnostics or culture are more inflammatory than other episodes of diarrhea and may require appropriate antibiotic treatment.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is characterized by prepubertal abrupt onset of obsessive-compulsive disorder (OCD). The sine qua non is group A streptococcus (GAS) infection, which is hypothesized to elicit an IgG-class anti-GAS antibody response that cross-reacts with antigens in the basal ganglia. However, the association between GAS antibody (GAS-IgG) levels and PANDAS has been inconsistent, and qualitative differences in GAS-IgG profiles have not been carefully evaluated in well-phenotyped cohorts. Moreover, independent studies have yet to converge on anti-neural autoantibodies that are specific to PANDAS. Here, we used phage display immunoprecipitation sequencing (PhIP-Seq) to perform ultra-deep anti-pathogen antibody repertoire profiling of serum from definitive pediatric PANDAS patients (N = 34) collected as part of a prior double-blind, placebo-controlled clinical trial of intravenous immunoglobulin (IVIg). PANDAS cases were compared to pediatric controls without a history of neuropsychiatric illness (N = 31). To assess for objective evidence of neuroglial injury, serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels were compared to healthy pediatric controls. Within PANDAS, NfL and GFAP levels were compared between pre- and post-treatment sera. To evaluate for central autoantibodies, a subset of baseline cerebrospinal fluid (CSF) samples (N = 25) was profiled by full-length human protein microarray. Though GAS reactivity by PhIP-Seq was well correlated with clinical anti-DNaseB and anti-streptolysin O titers, there were no quantitative or qualitative differences in GAS-IgG profiles between PANDAS and controls. Furthermore, NfL and GFAP levels did not differ between cases and controls. Within PANDAS, changes in NfL or GFAP levels at six weeks did not differ between placebo and IVIg groups. However, CSF autoantibody profiling by protein microarray revealed infrequent but notable candidate autoantibodies. In one patient, we identified autoantibodies against Argonaute family proteins (AGO-IgG), a marker of autoimmune sensory neuropathy. Longitudinal measurement of AGO-IgG in sera revealed that titers were unchanged after placebo, but decreased after IVIg, coinciding with symptomatic improvement, including a decrease in that patients CY-BOCS score. Overall, these results do not support an etiologic role for GAS-IgG in PANDAS. However, some individuals diagnosed with PANDAS may harbor anti-neural autoantibodies.

Background and Objectives: SARS-CoV-2 (COVID-19) continues to mutate, circulate, and adversely impact health and quality of life. While COVID-19 vaccines remain safe and effective, uptake remains low, especially among children, the youngest of whom were not vaccine-eligible until after Omicron and are underrepresented in published research. This study estimated vaccine effectiveness (VE) among under-5-year-olds. Methods: We used Virginia Department of Health surveillance data from June 2022 through October 2022 to conduct a test negative case-control study. We estimated VE derived from odds ratios (ORs) of reported infections using logistic regression among children aged 6-months to 5-years. Results: Using the earliest positive (cases) or negative (controls) post-vaccine-eligible test results, the VE associated with two doses of a COVID-19 vaccine was 78% (95% CI=45%, 93%; p=0.004) in unadjusted analyses and 70% (95% CI=25%, 91%, p=0.023) when adjusting for age, sex, prior testing behavior, and prior reported infections. The adjusted VE was 74% (95% CI=28%, 94%; p=0.025) among those with no prior positives reported and 45% (95% CI=-302%, 97%; p=0.569) among those with a prior positive reported. Conclusions: These results show that even though the vaccine was not closely matched to the dominant variants circulating during the time period analyzed, it was effective at reducing the risk of reported infections. This study adds to the body of knowledge on pediatric COVID-19 VE in an underrepresented age-group and in a rural region, illustrates the utility of surveillance data for evaluation, and can inform vaccine decisions to improve vaccine uptake for young children.

Background Klebsiella pneumoniae is a leading cause of sepsis in young infants. We evaluated the association of invasive K. pneumoniae disease (iKPnD) in relation to antigen-specific immunoglobulin G (IgG) and serum bactericidal activity (SBA) to four polysaccharide capsular (K) serotypes and five lipopolysaccharide (O) serotypes, as well as IgG to MrkA, in infants less than 90 days of age. Methods We conducted a retrospective case-control study in Kenyan and South African infants with blood culture-confirmed iKPnD. Serotype-specific antigen IgG concentrations of cases were compared with hospitalised controls without iKPnD. Geometric mean concentrations (GMCs) were estimated, and scaled covariate-adjusted models were used to estimate risk reduction over a grid of antibody concentrations. Results Transplacental transfer of IgG against various K. pneumoniae antigens increased with advancing gestational age. Serum IgG GMCs (expressed in RLU/mL) to disease-causing homotypic K- or O-serotypes were lower in cases compared with controls for anti-K2 (396 [95%CI: 250-628] vs 660 [95%CI: 562-776]), anti-K25 (396 [95%CI: 251-623 ] vs 1170 [95%CI: 988-1385]), anti-K149 (327 [95%CI: 204-521] vs 492 [95%CI: 435-557]); as well as anti-O1{beta},2 IgG (1282 [95%CI: 782-2101] vs 2250 [95%CI:1904-2658]). Furthermore, overall anti-MrkA IgG was lower in cases (945; 95%CI: 757-1179) compared with controls (1610; 95%CI: 1378-1880). SBA titres (expressed as IC50) did not differ between case and controls by K types, but were lower for O1{beta},2{beta} in cases (27; 95%CI: 12-63 vs. 136; 95% CI: 84-221). Conclusion Our findings provide preliminary evidence that low antibodies against three of four K-antigens, O1{beta},2{beta} and MrkA are inversely associated with iKPnD, and should be explored as potential vaccine antigens.

Background Nirsevimab has been widely administered in the United States since 2023 to protect infants and young children from severe disease caused by respiratory syncytial virus (RSV). Although early post-licensure studies have shown high effectiveness against medically attended RSV infection, uncertainty remains about the durability of protection, effectiveness beyond the first RSV season, and the extent to which changing RSV seasonality influences real-world effectiveness. Objective To estimate the effectiveness of nirsevimab against medically attended RSV infection across three consecutive RSV seasons and to examine how effectiveness varies by season and time since immunization. Methods We conducted a test-negative case-control study utilizing electronic health records of infants and young children tested for RSV by polymerase chain reaction in outpatient and inpatient settings within the Yale New Haven Health System between October 1, 2023, and March 1, 2026. Effectiveness of nirsevimab was estimated using multivariable logistic regression, adjusting for age, weekly RSV activity, pre-existing risk factors, and other potential confounders. Variation in effectiveness was examined by season, encounter setting, and time since immunization up to 24 months. Results Overall, 17,755 infants and young children were tested for RSV infection, of whom 2,388 (13.4%) were cases and 15,367 (86.6%) were controls. The overall effectiveness of nirsevimab was 67.3% (95% confidence interval [CI]: 59.8, 73.3%) against all medically-attended RSV infections, 60.2% (95% CI: 49.6, 68.5%) against RSV-associated outpatient visits, and 88.9% (95% CI: 82.3, 93.0%) against RSV-associated hospitalization. Effectiveness against medically attended RSV infection declined across seasons, from 76.7% (95% CI: 60.5, 86.3%) in 2023/24 to 54.4% (95% CI: 33.0, 68.9%) in 2025/26. Lower season-specific effectiveness in later seasons corresponded with progressively delayed RSV activity over. Protection against RSV-associated hospitalization declined with increasing time since immunization, from 92.5% (95% credible interval [CrI]: 85.9, 96.4%) at 1 month, to 77.2% (95% CrI: 60.4, 87.6%) at 6 months, and 39.9% (95% CrI: 2.4, 63.3%) at 12 months post-immunization, after which effectiveness plateaued. Conclusions Nirsevimab remained effective against RSV-associated hospitalization through 6 to 12 months after immunization. Delayed RSV activity was associated with lower effectiveness, highlighting the importance of aligning administration with local RSV circulation.

Preterm birth before 28 weeks remains a leading cause of neonatal mortality and long-term morbidity. Intrauterine infection-driven chorioamnionitis is strongly associated with preterm labor, fetal inflammatory response syndrome, and neonatal lung disease. Ureaplasma species are among the most common organisms isolated in chorioamnionitis and are frequently detected in the placenta, amniotic fluid, and respiratory tract of preterm infants. Clinical and experimental data implicate Ureaplasma exposure in early lung inflammation, impaired alveolar development, and bronchopulmonary dysplasia (BPD), yet the pathogenic events preceding microbial invasion of the amniotic cavity or fetal tissues remain poorly defined. To characterize early intrauterine and fetal lung inflammatory responses to localized choriodecidual U. parvum infection, we used a chronically catheterized pregnant rhesus macaque (Macaca mulatta) model. Time-mated animals underwent surgical placement of maternal, amniotic, and choriodecidual catheters and were inoculated with low-passage U. parvum serovar 1 or vehicle control at approximately 117 days gestational age. Placenta, fetal membranes, fetal plasma, and fetal lungs were assessed by qRT-PCR, multiplex cytokine assays, immunoblotting, immunohistochemistry, and trichrome staining to evaluate inflammatory signaling, inflammasome activation, prostaglandin pathways, immune cell infiltration, fibrosis, and lung maturation markers. Choriodecidual infection was confirmed in all inoculated animals. Amniotic fluid remained culture-and PCR-negative, and fetal lungs were largely free of detectable bacterial DNA. Despite the absence of intra-amniotic infection, fetal lung cytokine profiling revealed broad pro-inflammatory activation, with elevated GM-CSF, IL-1{beta}, IL-6, IL-8, MIP-1/{beta}, MCP-1, VEGF and reduced IL-10 contrasting with a modest systemic response limited to elevated plasma IL-18. Fetal lungs showed increased immune cell infiltration, upregulation of NLRP3, PYCARD, and CASP1, and activation of SAPK/JNK and NF-{kappa}B signaling. Histopathology demonstrated increased alveolar macrophages and intra-alveolar neutrophils with minimal fibrosis. Surfactant gene expression was altered (increased SFTPA, decreased SFTPB), and elevated -SMA indicated early myofibroblast activation. Localized choriodecidual U. parvum infection induces fetal lung inflammation prior to detectable intra-amniotic infection, demonstrating that direct infection of the amniotic fluid or fetal lung is not required for the initiation of fetal pulmonary inflammation. These findings suggest that subclinical ascending infection may initiate fetal lung injury and increase susceptibility to postnatal respiratory morbidity associated with preterm birth.

Background Post-acute sequelae are well described following COVID-19 but may also occur after other respiratory infections and Aedes-borne infections. Evidence remains fragmented due to heterogeneity in study design, populations, and exposure, outcome, and follow-up definitions. Methods We synthesized and compared post-acute sequelae across influenza, RSV-ARI, dengue fever, chikungunya, Zika, and yellow fever. We searched five databases from inception to 25-08-2025 for articles quantifying risk, incidence, or rates of post-acute sequelae following these diseases. Eligible non-randomized observational studies assessed post-acute neurological, psychiatric, gastrointestinal, cardiovascular, respiratory, renal, musculoskeletal, autoimmune, or endocrine outcomes after confirmed infection. Risk of bias was assessed using ROBINS-E. Random-effects meta-analyses with restricted maximum likelihood estimation were conducted when comparable effect estimates were available (PROSPERO #CRD420251124994). Findings 51 studies were included, predominantly from high-income regions. Most were retrospective cohorts using ICD-coded diagnoses; prospective studies used laboratory-confirmed infections. Data sources, comparator groups, exposure definitions, outcome ascertainment, and follow-up periods varied substantially. Meta-analyses were feasible for RSV, influenza, and dengue fever. All RSV-ARI studies were pediatric and assessed infections during infancy, which were associated with higher pooled odds of physician-diagnosed asthma (OR:2.93 [95%CI: 2.12-4.06]). Influenza studies used COVID-19-positive comparators; pooled estimates showed lower risk for neurological (HR:0.82 [0.76-0.89]) and composite outcomes (RR:0.88 [0.82-0.95]), with other organ systems non-significant. Dengue fever studies spanned all ages and showed increased risks of anxiety (HR:1.34 [1.01-1.78]), dementia (HR:1.61 [1.10-2.35]), autoimmune (RR:1.39 [1.17-1.67]), cardiovascular (HR:1.51 [1.27-1.80]), psychiatric (HR:1.17 [1.07-1.28]), and any sequelae (HR:1.19 [1.13-1.25]) versus those without prior infection. Interpretations Post-acute sequelae contribute to overall disease burden following RSV-ARI and dengue fever. The evidence remains limited by heterogeneity in study design, exposure and outcome definitions, comparator selection, and follow-up duration. Greater standardization in study design and reporting is needed to improve comparability and strengthen causal inference.

Abstract Objectives: Following the COVID-19 pandemic, multiple countries reported a surge in invasive group A streptococcus (iGAS) infections. Posited explanations include reduced population immunity, increased respiratory virus co-infection, and emergence of hypervirulent GAS clones. To assess the relative contribution of these factors, we analyzed the epidemiology and genomics of 3,408 iGAS infections in Scotland. Methods: National surveillance data from 2014-2024 were analyzed to characterize iGAS incidence. Hybrid whole genome sequencing was used to comprehensively genetically characterize 404 emm1 isolates collected from invasive and tonsillitis infections. Results: iGAS incidence markedly increased in late 2022 and early 2023, disproportionately affecting children and older adults. This surge was not associated with a proportional increase in bacteremia but did coincide with increased influenza and respiratory syncytial virus infections. Genomic analyses found that emm1 post-pandemic isolates were not genetically distinct from pre-pandemic isolates in genome-wide polymorphisms, accessory genes including virulence and antimicrobial resistance determinants, mobile genetic elements, or chromosomal structural variants. Conclusions: The post-pandemic iGAS surge in Scotland was not associated with emergence of a novel hypervirulent emm1 clone. Instead, the epidemiologic and population genomic findings are consistent with increased host susceptibility following reduced pathogen exposure during the pandemic and increased respiratory virus co-infection as predominant contributing factors.

Objective: Upper respiratory infections (URI) are the major trigger of asthma exacerbations in children with asthma and are more likely to be reported by Black and Mexican American children compared to White children in the US. We aimed to evaluate the extent to which obesity, nicotine exposure, household size, and socioeconomic status (SES) explained this excess URI risk among all children and among children with asthma. Study Design: Data collected on children aged 6-17 years from the National Health and Nutritional Examination Survey (2007-2012) were analyzed using survey weights and a mediation approach. Household SES was analyzed as a cumulative score reflecting income poverty ratio, education, and rental housing. URI was defined as cough, cold, phlegm, runny nose, or other respiratory illness (excluding hay fever and allergies) in the past 7 days. Results: Obesity and serum cotinine, a marker of nicotine exposure, explained little to none of the excess risk of URI while SES explained 36.4% (95% CI=34.1, 38.6) in Black and 28.5% (95% CI=26.7, 30.5) in Mexican American children. Living in rental housing and income poverty ratio<2, explained half (49.6%, 95% CI=46.9-52.3) and 20% (19.7%, 95% CI=18.9-20.5) of the excess URI risk among Black children, respectively. In Mexican American children, rental housing and low educational attainment each explained approximately 15-17% of the excess URI risk. Results were comparable among children with asthma. Conclusions: Markers of poverty, such as rental housing, contributed substantially to the excess risk of URI among Black and Mexican American children, including among those with asthma.

Background: Group A streptococcal (GAS) pharyngitis drives substantial antibiotic prescribing in children. The 10-day standard burdens adherence and prolongs exposure, increasing selective pressure for resistance. Yet, whether shorter courses achieve comparable outcomes remains unresolved. Purpose: To address how the duration of oral antibiotics affects clinical outcomes in children and adolescents with suspected or confirmed GAS pharyngitis. Data Sources: MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to July 2025. Reviewers also searched reference lists of eligible trials and relevant systematic reviews. Study Selection: Randomized trials enrolling children and adolescents [&le;]18 years with suspected or confirmed GAS pharyngitis comparing different durations of oral antibiotics, or oral antibiotics against placebo or no treatment. Data Extraction: Paired reviewers independently screened records, extracted data, and assessed risk of bias. Data Synthesis: We performed random-effects dose-response meta-analyses with restricted cubic splines and rated the certainty of evidence using GRADE. Forty-five trials enrolling 22,636 participants met eligibility criteria. Across outcomes, low to moderate certainty evidence suggests that 3, 5, and 10 days of antibiotic treatment may produce little to no difference. Moderate certainty evidence supports similar effects of 5 and 10 days on clinical cure, relapse, and adverse events. Evidence comparing 3 and 10 days carries lower certainty. Serious adverse events were rare: no deaths, 4 cases of acute rheumatic fever, and 4 cases of post-streptococcal glomerulonephritis among 776, 8,818, and 9,096 participants, respectively, making clinically important differences across treatment durations unlikely. Limitations: Evidence on 3-day courses came almost exclusively from trials of azithromycin, limiting inference about shorter penicillin regimens. Findings apply most directly to high-income settings. Conclusion: These findings challenge the long-standing 10-day standard for pediatric GAS pharyngitis and show that 5 days of oral antibiotics are likely as effective and safe as 10 days.