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BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic disrupted respiratory syncytial virus (RSV) seasonality. To optimize the use and evaluation of RSV infant immunization strategies, monitoring changes in RSV epidemiology is essential. METHODS: Hospitalizations for acute respiratory infections (ARIs) and RSV-coded ARI in children <2 years were extracted in 4 European hospitals, according to predefined case definitions (International Classification of Diseases, Tenth Revision codes). Prepandemic RSV seasons (2017-2018 to 2019-2020) were compared to 2021-2022 and 2022-2023. RESULTS: In 2021-2022 and 2022-2023, the peak number of RSV hospitalizations was higher than prepandemic peaks after short periods of RSV circulation, and lower than prepandemic peaks after long periods of RSV circulation. A greater proportion of RSV hospitalizations occurred in children 1 to <2 years in 2021-2022 in the Netherlands (18% vs 9%, P = .04). No increase in age was observed elsewhere. High-risk children represented a greater proportion of RSV hospitalizations during the pandemic. The proportion of pediatric intensive care unit admissions did not increase. CONCLUSIONS: A decrease in population immunity has been linked to older age at RSV hospitalization. We did not observe an increase in age in 3 of the 4 participating countries. Broad age categories may have prevented detecting an age shift. Monitoring RSV epidemiology is essential as Europe implements RSV immunization.
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BACKGROUND: During the first year of life, 1 in 4 infants develops a symptomatic respiratory syncytial virus (RSV) infection, yet only half seek medical attention. The current focus on medically attended RSV therefore underrepresents the true societal burden of RSV. We assessed the burden of nonmedically attended RSV infections and compared with medically attended RSV. METHODS: We performed active RSV surveillance until the age of 1 year in a cohort (n = 993) nested within the Respiratory Syncytial Virus Consortium in EUrope (RESCEU) prospective birth cohort study enrolling healthy term-born infants in 5 European countries. Symptoms, medication use, wheezing, and impact on family life were analyzed. RESULTS: For 97 of 120 (80.1%) nonmedically attended RSV episodes, sufficient data were available for analysis. In 50.5% (49/97), symptoms lasted ≥15 days. Parents reported impairment in usual daily activities in 59.8% (58/97) of episodes; worries, 75.3% (73/97); anxiety, 34.0% (33/97); and work absenteeism, 10.8% (10/93). Compared with medically attended RSV (n = 102, 9 hospital admissions), Respiratory Syncytial Virus NETwork (ReSViNET) severity scores were lower (3.5 vs 4.6, P < .001), whereas duration of respiratory symptoms and was comparable. CONCLUSIONS: Even when medical attendance is not required, RSV infection poses a substantial burden to infants, families, and society. These findings are important for policy makers when considering the implementation of RSV immunization. Clinical Trials Registration. ClinicalTrials.gov (NCT03627572).
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Lactante , Humanos , Estudios de Cohortes , Estudios Prospectivos , Europa (Continente)/epidemiología , HospitalizaciónRESUMEN
Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.
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Linfohistiocitosis Hemofagocítica , Síndrome de Respuesta Inflamatoria Sistémica , Trombocitopenia , Humanos , Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/genética , Niño , Masculino , Preescolar , Femenino , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Trombocitopenia/sangre , Trombocitopenia/inmunología , Lactante , Adolescente , Fenotipo , Proteómica , COVID-19/inmunología , COVID-19/sangre , COVID-19/complicacionesRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTIs) in infants. Maternal RSV vaccination is a preventive strategy of great interest, as it could have a substantial impact on infant RSV disease burden. In recent years, the clinical development of maternal RSV vaccines has advanced rapidly. OBJECTIVES: To assess the efficacy and safety of maternal respiratory syncytial virus (RSV) vaccination for preventing RSV disease in infants. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register and two other trials registries on 21 October 2022. We updated the search on 27 July 2023, when we searched MEDLINE, Embase, CENTRAL, CINAHL, and two trials registries. Additionally, we searched the reference lists of retrieved studies and conference proceedings. There were no language restrictions on our searches. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing maternal RSV vaccination with placebo or no intervention in pregnant women of any age. The primary outcomes were hospitalisation with clinically confirmed or laboratory-confirmed RSV disease in infants. The secondary outcomes covered adverse pregnancy outcomes (intrauterine growth restriction, stillbirth, and maternal death) and adverse infant outcomes (preterm birth, congenital abnormalities, and infant death). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (25 study reports) involving 17,991 pregnant women. The intervention was an RSV pre-F protein vaccine in four studies, and an RSV F protein nanoparticle vaccine in two studies. In all studies, the comparator was a placebo (saline, formulation buffer, or sterile water). We judged four studies at overall low risk of bias and two studies at overall high risk (mainly due to selection bias). All studies were funded by pharmaceutical companies. Maternal RSV vaccination compared with placebo reduces infant hospitalisation with laboratory-confirmed RSV disease (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.31 to 0.82; 4 RCTs, 12,216 infants; high-certainty evidence). Based on an absolute risk with placebo of 22 hospitalisations per 1000 infants, our results represent 11 fewer hospitalisations per 1000 infants from vaccinated pregnant women (15 fewer to 4 fewer). No studies reported infant hospitalisation with clinically confirmed RSV disease. Maternal RSV vaccination compared with placebo has little or no effect on the risk of congenital abnormalities (RR 0.96, 95% CI 0.88 to 1.04; 140 per 1000 with placebo, 5 fewer per 1000 with RSV vaccination (17 fewer to 6 more); 4 RCTs, 12,304 infants; high-certainty evidence). Maternal RSV vaccination likely has little or no effect on the risk of intrauterine growth restriction (RR 1.32, 95% CI 0.75 to 2.33; 3 per 1000 with placebo, 1 more per 1000 with RSV vaccination (1 fewer to 4 more); 4 RCTs, 12,545 pregnant women; moderate-certainty evidence). Maternal RSV vaccination may have little or no effect on the risk of stillbirth (RR 0.81, 95% CI 0.38 to 1.72; 3 per 1000 with placebo, no difference with RSV vaccination (2 fewer to 3 more); 5 RCTs, 12,652 pregnant women). There may be a safety signal warranting further investigation related to preterm birth. This outcome may be more likely with maternal RSV vaccination, although the 95% CI includes no effect, and the evidence is very uncertain (RR 1.16, 95% CI 0.99 to 1.36; 6 RCTs, 17,560 infants; very low-certainty evidence). Based on an absolute risk of 51 preterm births per 1000 infants from pregnant women who received placebo, there may be 8 more per 1000 infants from pregnant women with RSV vaccination (1 fewer to 18 more). There was one maternal death in the RSV vaccination group and none in the placebo group. Our meta-analysis suggests that RSV vaccination compared with placebo may have little or no effect on the risk of maternal death (RR 3.00, 95% CI 0.12 to 73.50; 3 RCTs, 7977 pregnant women; low-certainty evidence). The effect of maternal RSV vaccination on the risk of infant death is very uncertain (RR 0.81, 95% CI 0.36 to 1.81; 6 RCTs, 17,589 infants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The findings of this review suggest that maternal RSV vaccination reduces laboratory-confirmed RSV hospitalisations in infants. There are no safety concerns about intrauterine growth restriction and congenital abnormalities. We must be careful in drawing conclusions about other safety outcomes owing to the low and very low certainty of the evidence. The evidence available to date suggests RSV vaccination may have little or no effect on stillbirth, maternal death, and infant death (although the evidence for infant death is very uncertain). However, there may be a safety signal warranting further investigation related to preterm birth. This is driven by data from one trial, which is not fully published yet. The evidence base would be much improved by more RCTs with substantial sample sizes and well-designed observational studies with long-term follow-up for assessment of safety outcomes. Future studies should aim to use standard outcome measures, collect data on concomitant vaccines, and stratify data by timing of vaccination, gestational age at birth, race, and geographical setting.
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Ensayos Clínicos Controlados Aleatorios como Asunto , Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Mortinato , Humanos , Embarazo , Femenino , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Vacunas contra Virus Sincitial Respiratorio/uso terapéutico , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Lactante , Recién Nacido , Mortinato/epidemiología , Nacimiento Prematuro/prevención & control , Nacimiento Prematuro/epidemiología , Complicaciones Infecciosas del Embarazo/prevención & control , Hospitalización/estadística & datos numéricos , Retardo del Crecimiento Fetal/prevención & control , Resultado del Embarazo , Vacunación , Anomalías Congénitas/prevención & control , Sesgo , Muerte del Lactante/prevención & controlRESUMEN
Down syndrome (DS) is characterized by lowered immune competence and premature aging. We previously showed decreased antibody response following SARS-CoV-2 vaccination in adults with DS. IgG1 Fc glycosylation patterns are known to affect the effector function of IgG and are associated with aging. Here, we compare total and anti-spike (S) IgG1 glycosylation patterns following SARS-CoV-2 vaccination in DS and healthy controls (HC). Total and anti-Spike IgG1 Fc N-glycan glycoprofiles were measured in non-exposed adults with DS and controls before and after SARS-CoV-2 vaccination by liquid chromatography-mass spectrometry (LC-MS) of Fc glycopeptides. We recruited N = 44 patients and N = 40 controls. We confirmed IgG glycosylation patterns associated with aging in HC and showed premature aging in DS. In DS, we found decreased galactosylation (50.2% vs. 59.0%) and sialylation (6.7% vs. 8.5%) as well as increased fucosylation (97.0% vs. 94.6%) of total IgG. Both cohorts showed similar bisecting GlcNAc of total and anti-S IgG1 with age. In contrast, anti-S IgG1 of DS and HC showed highly comparable glycosylation profiles 28 days post vaccination. The IgG1 glycoprofile in DS exhibits strong premature aging. The combination of an early decrease in IgG1 Fc galactosylation and sialylation and increase in fucosylation is predicted to reduce complement activity and decrease FcγRIII binding and subsequent activation, respectively. The altered glycosylation patterns, combined with decreased antibody concentrations, help us understand the susceptibility to severe infections in DS. The effect of premature aging highlights the need for individuals with DS to receive tailored vaccines and/or vaccination schedules.
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Envejecimiento Prematuro , Síndrome de Down , Inmunoglobulina G , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Glicosilación , Femenino , Masculino , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/inmunología , Adulto , Persona de Mediana Edad , Síndrome de Down/inmunología , Síndrome de Down/metabolismo , COVID-19/inmunología , COVID-19/metabolismo , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Vacunación , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , GlicoproteínasRESUMEN
Background: The implementation of the approved respiratory syncytial virus (RSV) preventive interventions in immunisation programmes is advancing rapidly. Insight into healthcare costs of RSV-related paediatric intensive care unit (PICU) admissions is lacking, but of great importance to evaluate the impact of implementation. Therefore, this study aimed to determine the total annual RSV-related paediatric intensive care healthcare costs in the Netherlands. Methods: A nationwide prospective, observational, multicenter study was performed from September 2021 until June 2023. The total annual RSV-related healthcare costs on PICUs in the Netherlands were calculated using RSV-related costs (subgroup I) and consequential costs (subgroup II and III). Subgroup I comprised all PICU admitted infants ≤12 months of age with laboratory-confirmed RSV infection. Subgroup II and III consisted of postponed elective PICU admissions and refused acute PICU admissions due to RSV-related lack of PICU capacity. Findings: A total of 424 infants with RSV-related PICU admission were included. Median age at PICU admission was 46 days (IQR 25-89). The median length of PICU admission was 5 days (IQR 3-8). The total RSV-related PICU costs are 3,826,386 in 2021-2022, and 3,183,888 in 2022-2023. Potential costs averted by RSV preventive interventions is 1.9 to 2.6 million depending on season, and the duration of protection. Interpretation: RSV-related PICU admissions cost 3.1 to 3.8 million in the Netherlands during one season. The introduction of new RSV preventive interventions into the Dutch immunisation programme will generate significant cost-savings on PICUs and decreases the admission burden of PICUs. Funding: None.
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OBJECTIVES: Children are generally considered main drivers of transmission for respiratory viruses, but the emergence of SARS-CoV-2 challenged this paradigm. Human rhinovirus (RV) continued to co-circulate throughout the pandemic, allowing for direct comparison of age-specific infectivity and susceptibility within households between these viruses during a time of low SARS-CoV-2 population immunity. METHODS: Households with children were prospectively monitored for ≥23 weeks between August 2020 and July 2021. Upon onset of respiratory symptoms in a household, an outbreak study was initiated, including questionnaires and repeated nasal self-sampling in all household members. Swabs were tested by PCR. Age-stratified within-household secondary attack rates (SARs) were compared between SARS-CoV-2 and RV. RESULTS: A total of 307 households participated, including 582 children and 627 adults. Overall, SAR was lower for SARS-CoV-2 than for RV (aOR 0.55) and age distributions differed between both viruses (p < 0.001). Following household exposure, children were significantly less likely to become infected with SARS-CoV-2 compared to RV (aOR 0.16), whereas this was opposite in adults (aOR 1.71). CONCLUSION: In households, age-specific susceptibility to SARS-CoV-2 and RV differs and drives differences in household transmission between these pathogens. This highlights the importance of characterizing age-specific transmission risks, particularly for emerging infections, to guide appropriate infection control interventions.
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COVID-19 , Composición Familiar , Rhinovirus , SARS-CoV-2 , Humanos , COVID-19/transmisión , COVID-19/epidemiología , Rhinovirus/aislamiento & purificación , Adulto , Niño , Femenino , Masculino , SARS-CoV-2/aislamiento & purificación , Preescolar , Adolescente , Persona de Mediana Edad , Adulto Joven , Lactante , Estudios Prospectivos , Infecciones por Picornaviridae/transmisión , Infecciones por Picornaviridae/epidemiología , Factores de Edad , Anciano , PandemiasRESUMEN
Respiratory syncytial virus is the major cause of acute lower respiratory tract infections in young children, causing extensive mortality and morbidity globally, with limited therapeutic or preventative options. Cathelicidins are innate immune antimicrobial host defence peptides and have antiviral activity against RSV. However, upper respiratory tract cathelicidin expression and the relationship with host and environment factors in early life, are unknown. Infant cohorts were analysed to characterise early life nasal cathelicidin levels, revealing low expression levels in the first week of life, with increased levels at 9 months which are comparable to 2-year-olds and healthy adults. No impact of prematurity on nasal cathelicidin expression was observed, nor were there effects of sex or birth mode, however, nasal cathelicidin expression was lower in the first week-of-life in winter births. Nasal cathelicidin levels were positively associated with specific inflammatory markers and demonstrated to be associated with microbial community composition. Importantly, levels of nasal cathelicidin expression were elevated in infants with mild RSV infection, but, in contrast, were not upregulated in infants hospitalised with severe RSV infection. These data suggest important relationships between nasal cathelicidin, upper airway microbiota, inflammation, and immunity against RSV infection, with interventional potential.
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Catelicidinas , Infecciones por Virus Sincitial Respiratorio , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/metabolismo , Humanos , Femenino , Masculino , Lactante , Recién Nacido , Virus Sincitial Respiratorio Humano/inmunología , Mucosa Nasal/metabolismo , Mucosa Nasal/virología , Mucosa Nasal/inmunologíaRESUMEN
Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DRLow , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DRLow B cells in severe RSV disease. HLA-DRLow monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification.