Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants.

BACKGROUND: The safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)-associated lower respiratory tract infection when administered in healthy infants are unclear. METHODS: In a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen. RESULTS: A total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P = 0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P = 0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P = 0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group. CONCLUSIONS: Nirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510).

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.

A Genome-Wide Association Study of Respiratory Syncytial Virus Infection Severity in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide. Most children experience at least one 1 RSV infection by the age of two 2 years, but not all develop severe disease. However, the understanding of genetic risk factors for severe RSV is incomplete. Consequently, we conducted a genome-wide association study of RSV severity. METHODS: Disease severity was assessed by the ReSVinet scale, in a cohort of 251 infants aged 1 week to 1 year. Genotyping data were collected from multiple European study sites as part of the RESCEU Consortium. Linear regression models were used to assess the impact of genotype on RSV severity and gene expression as measured by microarray. RESULTS: While no SNPs reached the genome-wide statistical significance threshold (P < 5 × 10-8), we identified 816 candidate SNPs with a P-value of <1 × 10-4. Functional annotation of candidate SNPs highlighted genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Moreover, SNPs within the RAB27A locus significantly altered gene expression (false discovery rate, FDR P < .05). CONCLUSIONS: These findings may provide insights into genetic mechanisms driving severe RSV infection, offering biologically relevant information for future investigations.

The Clinical and Economic Burden of Antibiotic Use in Pediatric Patients with Varicella Infection: a Retrospective Cohort Analysis of Real-World Data in England.

BACKGROUND: Varicella is a highly infectious disease, particularly affecting children, that can lead to complications requiring antibiotics or hospitalization. Antibiotic use for varicella management is poorly documented. This study assessed antibiotic use for varicella and its complications in a pediatric population in England. METHODS: Data were drawn from medical records in the Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Patients <18 years old diagnosed with varicella during 2014-2018 with 3-month follow-up available were included. We described varicella-related complications, medication use, healthcare resource utilization, and costs from diagnosis until 3-month post-diagnosis. RESULTS: We identified 114,578 children with a primary varicella diagnosis. 7.7% (n = 8,814) had a varicella-related complication, the most common being ear, nose, and throat related (37.1%, n = 3,271). In all, 25.9% (n = 29,706/114,578) were prescribed antibiotics. A higher proportion of patients with complications than those without complications were prescribed antibiotics (64.3%, n = 5,668/8,814 vs. 22.7%, n = 24,038/105,764). Mean annualized varicella-related costs were £2,231,481 for the study cohort. Overall, antibiotic prescriptions cost ∼£262,007. CONCLUSIONS: This study highlights high antibiotic use and healthcare resource utilization associated with varicella management, particularly in patients with complications. A national varicella vaccination program in England may reduce varicella burden and related complications, medication use, and costs.

The disease burden of respiratory syncytial virus in Infants.

PURPOSE OF REVIEW: To describe the current global burden of respiratory syncytial virus (RSV) in infants and its implications for morbidity, health resources and economic costs. RECENT FINDINGS: New prophylactic therapies are on the horizon for RSV in the form of long-acting monoclonal antibodies suitable for healthy infants and maternal immunizations. SUMMARY: Despite being responsible for significant global infant morbidity and mortality, until recently there have been no effective therapeutics available for healthy infants to protect them from RSV. Several new drugs are likely to be available within the next few years which could help relieve a huge burden on healthcare systems over the coming winters.

National point-prevalence survey of healthcare-associated infections and antimicrobial use: UK-PAS/UKHSA joint call to action for all paediatric services.

The negative impact of high antimicrobial use (AMU), antimicrobial resistance and healthcare-associated infections (HCAIs) on children is concerning. However, a lack of available paediatric data makes it challenging to design and implement interventions that would improve health outcomes in this population, and impedes efforts to secure additional resources. The upcoming 2023 national point-prevalence survey of HCAIs and AMU in hospitals, led by the UK Health Security Agency, is an opportunity to collect valuable information, which will enable healthcare providers and policy makers to optimize antimicrobial stewardship and infection prevention practices in all populations, including children. These data will facilitate benchmarking and sharing of best practice, internally, nationally and internationally. This is a joint call to action asking all healthcare professionals-particularly in paediatrics-to nominate a lead for their institution and participate in this survey, to ensure appropriate paediatric representation, and help protect children from these growing threats.

Clinical and Viral Factors Associated With Disease Severity and Subsequent Wheezing in Infants With Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants and young children worldwide. Here we evaluated host demographic and viral factors associated with RSV disease severity in 325 RSV-infected infants under 1 year of age from 3 European countries during 2017-2020. Younger infants had a higher clinical severity (ReSViNET) score and were more likely to require hospitalization, intensive care, respiratory support, and/or mechanical ventilation than older infants (<3 months vs 3 to <6 months and 3 to <6 months vs ≥6 months). Older age (≥6 months vs <3 months), higher viral load, and RSV-A were associated with a greater probability of fever. RSV-A and RSV-B caused similar disease severity and had similar viral dynamics. Infants with a more severe RSV infection, demonstrated by having a higher ReSViNET score, fever, and requiring hospitalization and intensive care, were more likely to have developed subsequent wheezing at 1 year of age. CLINICAL TRIALS REGISTRATION: NCT03756766.

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Biomarkers for Disease Severity in Children Infected With Respiratory Syncytial Virus: A Systematic Literature Review.

BACKGROUND: Clinical manifestations of respiratory syncytial virus (RSV) infection vary widely from mild, self-limiting illness to severe life-threatening disease. There are gaps in knowledge of biomarkers to objectively define severe disease and predict clinical outcomes. METHODS: A systematic search was performed, 1945-March 2019 in databases Ovid Medline, Embase, Global health, Scopus, and Web of Science. Risk of bias was assessed using the Cochrane tool. RESULTS: A total of 25 132 abstracts were screened and studies were assessed for quality, risk of bias, and extracted data; 111 studies met the inclusion criteria. RSV severity was correlated with antibody titers, reduced T and B cells, dysregulated innate immunity, neutrophil mobilization to the lungs and blood, decreased Th1 response, and Th2 weighted shift. Microbial exposures in respiratory tract may contribute to neutrophil mobilization to the lungs of the infants with severe RSV compared with mild RSV disease. CONCLUSIONS: Although a wide range of biomarkers have been associated with RSV disease severity, robust validated biomarkers are lacking. This review illustrates the broad heterogeneity of study designs and high variability in the definition of severe RSV disease. Prospective studies are required to validate biomarkers. Additional research investigating epigenetics, metabolomics, and microbiome holds promise for novel biomarkers.

Immunological and Inflammatory Biomarkers of Susceptibility and Severity in Adult Respiratory Syncytial Virus Infections.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults. METHODS: A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources. RESULTS: From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection. CONCLUSIONS: Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

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.

Participant retention in follow-up studies of prematurely born children.

BACKGROUND: Follow-up studies of infants born prematurely are essential to understand the long-term consequences of preterm birth and the efficacy of interventions delivered in the neonatal period. Retention of participants for follow-up studies, however, is challenging, with attrition rates of up to 70%. Our aim was to examine retention rates in two follow-up studies of prematurely born children and identify participant or study characteristics that were associated with higher attrition, and to discuss retention strategies with regard to the literature. METHODS: Data from children recruited at birth to one of two studies of prematurely born infants were assessed. The two studies were the United Kingdom Oscillation Study (UKOS, a randomised study comparing two modes of neonatal ventilation in infants born less than 29 weeks of gestational age (GA)), and an observational study examining the impact of viral lower respiratory tract infections in infancy in those born less than 36 weeks of GA (virus study). The UKOS participants, but not those in the virus study, had regularly been contacted throughout the follow-up period. UKOS subjects were followed up at 11 to 14 years of age and subjects in the virus study at 5-7 years of age. At follow up in both studies, pulmonary function and respiratory morbidity were assessed. Retention rates to follow-up in the two studies and baseline characteristics of those who were and were not retained were assessed. RESULTS: Retention was significantly higher in UKOS than the virus study (61% versus 35%, p < 0.0001). Subjects lost to UKOS follow up had greater deprivation scores (p < 0.001), a greater likelihood of intrauterine tobacco exposure (p = 0.001) and were more likely to be of non-white ethnicity (p < 0.001). In the virus study, those lost to follow-up had higher birth weights (p = 0.036) and were less likely to be oxygen dependent at hospital discharge (p = 0.003) or be part of a multiple birth (p = 0.048). CONCLUSIONS: Higher retention was demonstrated when there was regular contact in the follow-up period. Both social factors and initial illness severity affected the retention into follow-up studies of prematurely born infants, though these factors were not consistent across the two studies.

How to use respiratory viral studies.

Viral respiratory tract infections are the most common infections of childhood. They result in clinical syndromes ranging from mild upper respiratory tract infection to severe lower respiratory tract disease requiring intensive care. Respiratory viruses are most commonly identified from a respiratory swab or nasopharyngeal aspirate by real-time PCR, which has a very high sensitivity and specificity. In this article, we review when and how children should be tested for viral respiratory tract infections and how to interpret the result in context of the clinical picture.

Change in viral bronchiolitis management in primary care in the UK after the publication of NICE guideline.

The aim of this study was to investigate changes in general practitioner (GP) management before and after the publication of the National Institute for Health and Care Excellence bronchiolitis guideline. In March 2015 and May 2016, an electronic questionnaire was sent to GPs. It was completed by 1001 GPs in 2015 and 1009 in 2016. There were small but significant improvements in proportions of GPs using a guideline, measuring oxygen saturations and providing written guidance, and appropriate reductions in those prescribing medications. Thirty-five per cent had read the guideline and 25% changed their practice since guideline publication. There were modest but significant improvements in reported management by GPs after guideline publication.

Fifteen-minute consultation: enterovirus meningitis and encephalitis-when can we stop the antibiotics?

Enterovirus (EV) is the most common cause of aseptic meningitis and has a benign course, unlike EV encephalitis, which can result in long-term neurological sequelae. There are no active treatments or prophylactic agents, and management is purely supportive. Obtaining an EV-positive cerebrospinal fluid result usually allows antimicrobial treatment to be stopped. This review will answer some of the common questions surrounding EV meningitis/encephalitis.

Functional and genetic predisposition to rhinovirus lower respiratory tract infections in prematurely born infants.

Term born infants are predisposed to human rhinovirus (HRV) lower respiratory tract infections (LRTI) by reduced neonatal lung function and genetic susceptibility. Our aim was to investigate whether prematurely born infants were similarly predisposed to HRV LRTIs or any other viral LRTIs. Infants born less than 36 weeks of gestational age were recruited. Prior to neonatal/maternity unit discharge, lung function (functional residual capacity by helium gas dilution and multiple breath washout, lung clearance index and compliance (Crs), and resistance (Rrs) of the respiratory system) was assessed and DNA samples assessed for eight single nucleotide polymorphisms (SNPs) in seven genes: ADAM33, IL10, MMP16 NFκB1A,SFTPC, VDR, and NOS2A. Infants were prospectively followed until 1 year corrected age. Nasopharyngeal aspirates (NPAs) were sent whenever an infant developed a LRTI and tested for 13 viruses. One hundred and thirty-nine infants were included in the analysis. Infants who developed HRV LRTIs had reduced Crs (1.6 versus 1.2 mL/cmH2O/kg, p = 0.044) at 36 weeks postmenstrual age. A SNP in the gene coding for the vitamin D receptor was associated with the development of HRV LRTIs and any viral LRTIs (p = 0.02). CONCLUSION: Prematurely born infants may have both a functional and genetic predisposition to HRV LRTIs. What is Known: • Term born infants are predisposed to rhinovirus lower respiratory tract (HRV LRTIs) infection by reduced neonatal lung function. • Term born infants requiring hospitalisation due to HRV bronchiolitis were more likely to have single nucleotide polymorphism (SNP) in the IL-10 gene. What is New: • Prematurely born infants who developed a HRV LRTI had lower C rs before maternity unit discharge. • A SNP in the gene coding for the vitamin D receptor was associated with the development of HRV LRTIs and overall respiratory viral LRTIs in prematurely born infants.

Management of Respiratory Syncytial Virus Bronchiolitis: 2015 Survey of Members of the European Society for Paediatric Infectious Diseases.

In 1995, the European Society for Paediatric Infectious Diseases (ESPID) carried out a survey of its members to assess the variation in management of respiratory syncytial virus (RSV) bronchiolitis. The aim of the current study was to carry out a similar survey 20 years later to assess how the management had changed. An electronic, structured, English language survey, based on the United Kingdom National Institute for Health and Care Excellence (NICE) bronchiolitis draft guideline, was sent to ESPID members in March 2015. Questions asked included information on treatment practices of infants with bronchiolitis and doctor demographics. We received responses from 135 doctors (14% of the ESPID members) who worked in 115 hospitals. 56% of the doctors used a written guideline to manage bronchiolitic infants. All doctors stated that they isolated individually or in cohorts all hospitalised bronchiolitis infants. The level of oxygen saturation suggested as an indication to administer supplemental oxygen varied between <89% and <95%. We found significant reductions in the use of ribavirin, bronchodilators, and corticosteroids from 1995 to 2015 (ribavirin 57% to 13%, P < 0.0001; bronchodilators 95% to 82%, P = 0.0024; corticosteroids 81% to 45%, P < 0.0001). Although variability in management remains high, encouragingly significantly fewer doctors are prescribing ribavirin, bronchodilators, and corticosteroids compared to 20 years ago.