Inconsistent Increase in Age at Respiratory Syncytial Virus Hospitalization of Children Aged <2 Years During the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic: A Retrospective Multicenter Study in 4 European Countries.

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.

External Validation of the Discriminative Validity of the ReSVinet Score and Development of Simplified ReSVinet Scores in Secondary Care.

BACKGROUND: There is no consensus on how to best quantify disease severity in infants with respiratory syncytial virus (RSV) and/or bronchiolitis; this lack of a sufficiently validated score complicates the provision of clinical care and, the evaluation of trials of therapeutics and vaccines. The ReSVinet score appears to be one of the most promising; however, it is too time consuming to be incorporated into routine clinical care. We aimed to develop and externally validate simplified versions of this score. METHODS: Data from a multinational (the Netherlands, Spain, and United Kingdom) multicenter case-control study of infants with RSV were used to develop simplified versions of the ReSVinet score by conducting a grid search to determine the best combination of equally weighted parameters to maximize for the discriminative ability (measured by area under the receiver operating characteristic curve [AUROC]) across a range of outcomes (hospitalization, intensive care unit admission, ventilation requirement). Subsequently discriminative validity of the score for a range of secondary care outcomes was externally validated by secondary analysis of datasets from Rwanda and Colombia. RESULTS: Three candidate simplified scores were identified using the development dataset; they were excellent (AUROC >0.9) at discriminating for a range of outcomes, and their performance was not significantly different from the original ReSVinet score despite having fewer parameters. In the external validation datasets, the simplified scores were moderate to excellent (AUROC, 0.7-1) across a range of outcomes. In all outcomes, except in a single dataset for predicting admission to the high-dependency unit, they performed at least as well as the original ReSVinet score. CONCLUSIONS: The candidate simplified scores developed require further external validation in larger datasets, ideally from resource-limited settings before any recommendation regarding their use.

Substantial Burden of Nonmedically Attended RSV Infection in Healthy-Term Infants: An International Prospective Birth Cohort Study.

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).

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

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.

Outpatient respiratory syncytial virus infections and novel preventive interventions.

PURPOSE OF REVIEW: With interventions to prevent respiratory syncytial virus (RSV) infection within reach, this review aims to provide healthcare professionals with the latest information necessary to inform parents and assess the potential impact of RSV prevention on everyday practice. We address frequently asked questions for parental counseling. RECENT FINDINGS: Numerous studies emphasize the major burden of RSV on young children, parents, healthcare and society. In the first year of life, about 14% of healthy term infants visit a doctor and 2% require hospitalization due to RSV. In older children (1--5 years), RSV infections and associated morbidity (wheeze, acute otitis media) are major drivers of outpatient visits. A novel maternal RSV vaccine and long-acting mAb can provide protection during infants' first months of life. This maternal vaccine showed 70.9% efficacy against severe RSV infection within 150 days after birth; the mAb nirsevimab reduces medically attended RSV infections by 79.5% within 150 days after administration. Both gained regulatory approval in the USA (FDA) and Europe (EMA). SUMMARY: Novel RSV immunizations hold promise to reduce the RSV burden in infants, with substantial impact on everyday practice. Tailored parental guidance will be instrumental for successful implementation. Awaiting pediatric vaccines, RSV infections beyond infancy will still pose a significant outpatient burden.

Respiratory syncytial virus vaccination during pregnancy for improving infant outcomes.

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.

Year-Round Respiratory Syncytial Virus Transmission in The Netherlands Following the COVID-19 Pandemic: A Prospective Nationwide Observational and Modeling Study.

We initiated a nationwide prospective study to monitor respiratory syncytial virus (RSV)-related pediatric hospitalizations in 46 hospitals throughout the Netherlands between May 2021 and August 2022. We showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. We extended a dynamic simulation model to evaluate the impact of waning immunity on pediatric RSV hospitalizations in the Netherlands using 4 different scenarios. Our results suggest that the observed continuous RSV transmission pattern could be associated with waning immunity due to the period of very low RSV circulation during the COVID-19 pandemic.

Long term sequelae after SARS-CoV-2 infection in children: a household study.

BACKGROUND: In children persistent symptoms after SARS-CoV-2 infection have been reported, however, duration and characteristics of symptoms in previously healthy children remain unclear. Therefore this study aimed to evaluate persisting symptoms in children at 6 and 12 months after a SARS-CoV-2 infection. METHODS: In this prospective cohort study households with a confirmed SARS-CoV-2 positive outbreak were matched 1:1 to household controls from SARS-CoV-2 negative outbreaks. These households completed questionnaires at 6 and 12 months on the presence and severity of SARS-CoV-2 related symptoms, general well-being/functioning, cognition, persisting symptoms and quality of life. FINDINGS: None of the children who had a SARS-CoV-2 infection during the study reported persistent symptoms at 6 and 12 months after infection, whereas almost 8% of the children with a negative RT-PCR test during the study reported symptoms such as coughing and mild fever, however, no significant differences were found. In addition, for all other outcomes, no differences were observed between the two groups. TAKE HOME MESSAGE: Post-acute sequelae of mild SARS-CoV-2 infections appears to be uncommon in previously healthy children.

Patient Involvement in RSV Research: Towards Patients Setting the Research Agenda.

Respiratory syncytial virus (RSV) causes a substantial disease burden among children, elderly and immunocompromised adults. Recognition of patient involvement in research is gradually increasing. Most research is being carried out without active patient involvement other than patients participating as study subjects, and most knowledge gained through research only partially reaches the general public. Since 2016, the RSV Patient Advisory Board has officially been involved as an advisory group in the Respiratory Syncytial Virus Consortium in Europe (RESCEU). What started as a small single-center initiative, is now growing towards an international organization providing patient perspectives as inputs to scientists, and improving awareness of RSV. This article summarizes the history, current role, and future aims of the RSV Patient Advisory Board as an advocate to improve patient involvement in research. RSV patients and their representatives are important stakeholders in setting the global research agenda, and educating patients, professionals, and the general public.

Contact With Young Children Increases the Risk of Respiratory Infection in Older Adults in Europe-the RESCEU Study.

BACKGROUND: Knowledge about how older adults get a respiratory infection is crucial for planning preventive strategies. We aimed to determine how contact with young children living outside of the household affects the risk of acute respiratory tract infections (ARTI) in community-dwelling older adults. METHODS: This study is part of the European RESCEU older adult study. Weekly surveillance was performed to detect ARTI throughout 2 winter seasons (2017-2018, 2018-2019). Child exposure, defined as having regular contact with children under 5 living outside of the subject's household, was assessed at baseline. The average attributable fraction was calculated to determine the fraction of ARTI explained by exposure to these children. RESULTS: We prospectively established that 597/1006 (59%) participants experienced at least 1 ARTI. Child exposure increased the risk of all-cause ARTI (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.21 -2.08; P = .001). This risk was highest in those with the most frequent contact (aOR, 1.80; 95% CI, 1.23-2.63; P = .003). The average attributable fraction of child exposure explaining ARTI was 10% (95% CI, 5%-15%). CONCLUSIONS: One of 10 ARTI in community-dwelling older adults is attributable to exposure to preschool children living outside of the household. CLINICAL TRIALS REGISTRATION: NCT03621930.

World Health Organization Influenza-Like Illness Underestimates the Burden of Respiratory Syncytial Virus Infection in Community-Dwelling Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) surveillance is heavily dependent on the influenza-like illness (ILI) case definition from the World Health Organization (WHO). Because ILI includes fever in its syndromic case definition, its ability to accurately identify acute respiratory tract infections (ARTI) caused by RSV in older adults is uncertain. METHODS: The accuracy of the WHO ILI and a modified ILI (requiring only self-reported fever) case definitions in identifying patients with PCR-confirmed RSV-ARTI was evaluated in community-dwelling older adults (≥60 years) from the prospective European RESCEU cohort study. RESULTS: Among 1040 participants, 750 ARTI episodes were analyzed including 36 confirmed RSV-ARTI. Due to a general lack of fever, sensitivity for RSV-ARTI was 33% for modified ILI and 11% for ILI. The area under the curve for both ILI definitions was 0.52 indicating poor discrimination for RSV. RSV-ARTI could not be distinguished from all other ARTI based on clinical symptoms. CONCLUSIONS: The use of ILI underestimated the occurrence of RSV-ARTI in community-dwelling older adults up to 9-fold (11% sensitivity). Because worldwide RSV surveillance depends largely on ILI, there is an urgent need for a better approach to measure the occurrence of RSV disease and the impact of future RSV vaccine introduction. Clinical Trials Registration. NCT03621930.

Performance Assessment of a Rapid Molecular Respiratory Syncytial Virus Point-of-Care Test: A Prospective Community Study in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) causes a substantial burden in older adults. Viral load in RSV-infected adults is generally lower compared to young children, which could result in suboptimal sensitivity of RSV diagnostics. Although the Xpert® Xpress Flu/RSV assay has been used in routine clinical care, its sensitivity to diagnose RSV infection in older adults is largely unknown. We aimed to compare the performance of the Xpert® Xpress Flu/RSV assay with real-time reverse-transcription polymerase chain reaction (RT-PCR) in home-dwelling older adults (≥60 years of age). METHODS: Nasopharyngeal swabs were tested with Xpert® Xpress Flu/RSV and compared to RSV RT-PCR in older adults with acute respiratory tract infections with different levels of disease severity. RESULTS: We studied 758 respiratory samples from 561 older adults from 2 consecutive RSV seasons. Thirty-five (4.6%) samples tested positive for RSV by at least 1 of the assays, of which 2 samples were negative by Xpert® Xpress Flu/RSV and 3 samples by real-time RT-PCR. The positive percentage agreement (PPA) was 90.9% (95% confidence interval [CI], 76.4%-96.8%) and negative percentage agreement was 99.7% (95% CI, 99.0%-99.9%). Viral loads were low (≤103 copies/mL or cycle threshold value ≥34) in all cases with discordant results for the 2 assays. CONCLUSIONS: The PPA of Xpert® Xpress Flu/RSV compared to routine RT-PCR is high for RSV detection in home-dwelling older adults. The assay is fast and easy to use at the point of care. CLINICAL TRIALS REGISTRATION: NCT03621930.

Decreased Antibody Response After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Patients With Down Syndrome.

The risk of a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults with Down syndrome is increased, resulting in an up to 10-fold increase in mortality, in particular in those >40 years of age. After primary SARS-CoV-2 vaccination, the higher risks remain. In this prospective observational cohort study, SARS-CoV-2 spike S1-specific antibody responses after routine SARS-CoV-2 vaccination (BNT162b2, messenger RNA [mRNA]-1273, or ChAdOx1) in adults with Down syndrome and healthy controls were compared. Adults with Down syndrome showed lower antibody concentrations after 2 mRNA vaccinations or after 2 ChAdOx1 vaccinations. After 2 mRNA vaccinations, lower antibody concentrations were seen with increasing age. CLINICAL TRIALS REGISTRATION: NCT05145348.

Respiratory Syncytial Virus Consortium in Europe (RESCEU) Birth Cohort Study: Defining the Burden of Infant Respiratory Syncytial Virus Disease in Europe.

BACKGROUND: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI). METHODS: Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis. RESULTS: The primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI. CONCLUSIONS: We will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants. CLINICAL TRIALS REGISTRATION: NCT03627572.

Low Sensitivity of BinaxNOW RSV in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis. METHODS: We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard. RESULTS: One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%-16.5%) and a specificity of 100% (95% CI, 96.2%-100%). Sensitivity was low in all subgroups. CONCLUSIONS: We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution.

Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity. CLINICAL TRIALS REGISTRATION: NCT03756766.

Global molecular diversity of RSV - the "INFORM RSV" study.

BACKGROUND: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age. METHODS: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies. DISCUSSION: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.

RSV hospitalization in infancy increases the risk of current wheeze at age 6 in late preterm born children without atopic predisposition.

Severe respiratory syncytial virus (RSV) infection during infancy is associated with ongoing respiratory morbidity. In a large birth cohort of 2210 healthy preterm infants born at 32-35 weeks of gestation, we aimed to determine the role of atopy in the link between RSV hospitalization and current wheeze at age 6. We defined current wheeze as parent-reported wheeze or the use of respiratory medication in the past 12 months. Based on a positive family history of atopic disease, we distinguished between children with and without atopic predisposition. Six-year follow-up data was obtained in 997/1559 (64%) children of which 102 (10.2%) children had been hospitalized with RSV during infancy. Current wheeze was present in 184/997 (18.6%) children. RSV hospitalization was an independent risk factor for current wheeze in children without atopic predisposition (aOR 4.05 [95% CI 1.22-12.52]) but not in children with this atopic background (aOR 1.50 [95% CI 0.81-2.71]).Conclusion: This is the largest published birth cohort demonstrating that in late preterm infants, atopic predisposition defines the relationship between RSV hospitalization and current wheeze. Future RSV prevention trials aiming to prevent ongoing respiratory symptoms should be analyzed separately for atopic status. What is Known: • RSV infection is responsible for a significant burden of disease in young children worldwide. • Severe RSV infection in early life is associated with asthmatic symptoms later in life. What is New: • This is the largest published birth cohort reporting about the role of atopic predisposition in the link between severe RSV infection and current wheeze at school age. • We show that RSV hospitalization in infancy is an independent risk factor for current wheeze in late preterm children without atopic predisposition at age 6. This was not seen in children with atopic predisposition.

High frequency of Polio-like Enterovirus C strains with differential clustering of CVA-13 and EV-C99 subgenotypes in a cohort of Malawian children.

Enteroviruses (EVs) are among the most commonly detected viruses infecting humans worldwide. Although the prevalence of EVs is widely studied, the status of EV prevalence in sub-Saharan Africa remains largely unknown. The objective of our present study was therefore to increase our knowledge on EV circulation in sub-Saharan Africa. We obtained 749 fecal samples from a cross-sectional study conducted on Malawian children aged 6 to 60 months. We tested the samples for the presence of EVs using real time PCR, and typed the positive samples based on partial viral protein 1 (VP1) sequences. A large proportion of the samples was EV positive (89.9%). 12.9% of the typed samples belonged to EV species A (EV-A), 48.6% to species B (EV-B) and 38.5% to species C (EV-C). More than half of the EV-C strains (53%) belonged to subgroup C containing, among others, Poliovirus (PV) 1-3. The serotype most frequently isolated in our study was CVA-13, followed by EV-C99. The strains of CVA-13 showed a vast genetic diversity, possibly representing a new cluster, 'F'. The majority of the EV-C99 strains grouped together as cluster B. In conclusion, this study showed a vast circulation of EVs among Malawian children, with an EV prevalence of 89.9%. Identification of prevalences for species EV-C comparable to our study (38.5%) have only previously been reported in sub-Saharan Africa, and EV-C is rarely found outside of this region. The data found in this study are an important contribution to our current knowledge of EV epidemiology within sub-Saharan Africa.

Intravenous immunoglobulins in children with new onset dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy is a rare but serious disorder in children. No effective diagnostic or treatment tools are readily available. This study aimed to evaluate the efficacy of intravenous immunoglobulins in children with new onset dilated cardiomyopathy. Methods and results In this retrospective cohort study, 94 children with new onset dilated cardiomyopathy were followed during a median period of 33 months. All patients with secondary dilated cardiomyopathy - for example, genetic, auto-immune or structural defects - had been excluded. Viral tests were performed in all patients and 18 (19%) children met the criteria for the diagnosis "probable or definite viral myocarditis". Intravenous immunoglobulins were administered to 21 (22%) patients. Overall transplant-free survival was 75% in 5 years and did not differ between treatment groups. The treatment was associated with a higher recovery rate within 5 years, compared with non-treated children (70 versus 43%, log rank=0.045). After correction for possible confounders the hazard ratio for recovery with intravenous immunoglobulins was not significant (hazard ratio: 2.1; 95% CI: 1.0-4.6; p=0.056). Administration of intravenous immunoglobulins resulted in a greater improvement in the shortening fraction of the left ventricle. CONCLUSION: In our population of children with new onset dilated cardiomyopathy, of either viral or idiopathic origin, intravenous immunoglobulins were administered to a minority of the patients and did not influence transplant-free survival, but were associated with better improvement of systolic left ventricular function and with better recovery. Our results support the concept that children with new onset dilated cardiomyopathy might benefit from intravenous immunoglobulins.