Respiratory Syncytial Virus Monoclonal Antibody Research Articles

Advocacy for neonates: Will respiratory syncytial virus monoclonal antibodies and maternal vaccine be made available in India?

Respiratory syncytial virus (RSV)-related morbidity in children has been widely described. Research has led to the availability of palivizumab for decades in high-income countries. Ongoing research underlines the high priority given to this conundrum. Nirsevimab, a long-acting monoclonal antibody, and a maternal vaccine have been developed and approved for RSV. Neither of these are available in India. Improving the survival of extreme preterm neonates in our country should parallel other strategies to protect them from diseases that affect these high-risk neonates. This case series comprises sick RSV-infected infants from our centre over a single season. Of 187 young infants who presented to the Neonatology Department with features of viral lower respiratory infections, 9 (4.8%) required intensive care. All of them were positive for RSV by nasopharyngeal polymerase chain reaction. A total of 25 (13%) required hospitalisation. Preterm infants presented with apnea or severe respiratory distress. All 9 in the intensive care unit required respiratory support, and 8 needed invasive ventilation. The median duration of hospital stay for these infants was 18 (7–37) days. This report is an appeal to stakeholders towards making these evidence-based prophylactic methods available in India. A preventable problem in high-risk neonates could be reduced. Improving neonatal survival and outcomes calls for our country to be at par with high-income countries for RSV prevention. RSV-related morbidity is an endemic conundrum with a high disease burden. We could take prompt action, akin to efforts taken during the COVID-19 pandemic.

A Historical Perspective on Respiratory Syncytial Virus Prevention: A Journey Spanning Over Half a Century From the Setback of an Inactive Vaccine Candidate to the Success of Passive Immunization Strategy.

The efforts to prevent respiratory syncytial virus (RSV) infection in infants span over half a century. RSV vaccine development began in the 1960s, and it confronted a significant disappointment after testing a formalin-inactivated RSV (FI RSV) vaccine candidate. This inactivated RSV vaccine was not protective. A large number of the vaccinated RSV-naive children, when subsequently exposed to natural RSV infection from wild-type virus in the community, developed severe lung inflammation termed enhanced respiratory disease. This resulted in a halt in RSV vaccine development. In the 1990s, attention turned to the potential for passive protection against severe RSV disease with immunoglobulin administration. This led to studies on using standard intravenous immunoglobulins in high-risk infants, followed by high-titer RSV immunoglobulin preparation and, subsequently, the development of RSV monoclonal antibodies. Over the past 25 years, palivizumab has been recognized as a safe and effective monoclonal antibody as a prevention strategy for RSV in high-risk children. Its high cost and need for monthly administration, however, has hindered its use to ~2% of the birth cohort, neglecting the vast majority of newborns, including healthy full-term infants who comprise the largest portion of RSV hospitalizations and the greatest part of the burden of RSV disease. Still these efforts, helped pave the way for the present advances in RSV prevention that hold promise for mitigating severe RSV disease for all infants.

Risk Factors for Severe Respiratory Syncytial Virus Infection in Hospitalized Children.

Respiratory syncytial virus (RSV) is a common cause of bronchiolitis and pneumonia in infants and young children. Starting in December 2010, RSV monoclonal antibody (RSV mAb) was endorsed by Taiwan National Health Insurance and given to children with prematurity and/or congenital heart diseases, which are considered high-risk factors for severe RSV diseases. Investigating other important contributing risk factors is warranted. We conducted a cohort study at National Taiwan University Hospital to determine the rate of severe outcomes among children hospitalized due to RSV infection from 2008 to 2018. Adjusted for age, sex and birth cohorts born before and after RSV mAb endorsement, we identified risk factors for severe RSV infection, defined as the requirement of invasive ventilator support. There were 1985 admissions due to RSV infections. Among them, 66 patients (3.3%) had severe RSV infection. The proportion of severe RSV infections decreased significantly after RSV mAb endorsement. Multivariable analysis revealed that age <1.5 months and cardiovascular and congenital/genetic diseases were high-risk underlying conditions. In addition, bacterial coinfections, elevated creatinine levels and initial abnormal chest radiograph findings posed warning signs for severe RSV infection. Children younger than 1.5 months of age with cardiovascular or congenital/genetic diseases were predisposed to severe RSV infection and might benefit from RSV mAb prophylaxis.

Clinical research on RSV prevention in children and pregnant women: progress and perspectives.

Respiratory syncytial virus (RSV) is a significant causative agent of bronchitis and pneumonia in infants and children. The identification and structural analysis of the surface fusion glycoprotein of RSV represents a pivotal advancement in the development of RSV prevention. This review provides a comprehensive summary of RSV monoclonal antibody (mAb) and vaccine clinical trials registered on ClinicalTrials.gov, emphasizing on the classification, name, target, phase, clinical outcomes, and safety data of RSV vaccination in newborns, infants and children. We also discuss the characteristics of the types of RSV vaccines for maternal immunity and summarize the current clinical research progress of RSV vaccination in pregnant women and their protective efficacy in infants. This review will provide new ideas for the development of RSV prevention for children in the future.

Wastewater-based surveillance identifies start to the pediatric respiratory syncytial virus season in two cities in Ontario, Canada.

Detection of community respiratory syncytial virus (RSV) infections informs the timing of immunoprophylaxis programs and hospital preparedness for surging pediatric volumes. In many jurisdictions, this relies upon RSV clinical test positivity and hospitalization (RSVH) trends, which are lagging indicators. Wastewater-based surveillance (WBS) may be a novel strategy to accurately identify the start of the RSV season and guide immunoprophylaxis administration and hospital preparedness. We compared citywide wastewater samples and pediatric RSVH in Ottawa and Hamilton between August 1, 2022, and March 5, 2023. 24-h composite wastewater samples were collected daily and 5 days a week at the wastewater treatment facilities in Ottawa and Hamilton, Ontario, Canada, respectively. RSV WBS samples were analyzed in real-time for RSV by RT-qPCR. RSV WBS measurements in both Ottawa and Hamilton showed a lead time of 12 days when comparing the WBS data set to pediatric RSVH data set (Spearman's ρ = 0.90). WBS identify early RSV community transmission and declared the start of the RSV season 36 and 12 days in advance of the provincial RSV season start (October 31) for the city of Ottawa and Hamilton, respectively. The differing RSV start dates in the two cities is likely associated with geographical and regional variation in the incidence of RSV between the cities. Quantifying RSV in municipal wastewater forecasted a 12-day lead time of the pediatric RSVH surge and an earlier season start date compared to the provincial start date. These findings suggest an important role for RSV WBS to inform regional health system preparedness, reduce RSV burden, and understand variations in community-related illness as novel RSV vaccines and monoclonal antibodies become available.

The third pandemic: The respiratory syncytial virus landscape and specific considerations for the allergist/immunologist.

Background: Since its initial identification in 1956, respiratory syncytial virus (RSV) has been the second most common cause of mortality in infants <6 months of age and a major cause of morbidity and mortality associated with lower respiratory tract infection (LRTI) in older adults (ages >60 years) worldwide. Of particular interest to the allergist/immunologist is a growing body of evidence that suggests an association between LRTI caused by RSV in infants with later-life development of asthma, wheezing, or impaired lung function in adults. Efforts to develop a RSV vaccine have been thwarted for >70 years by the occurrence of enhanced respiratory disease (ERD), an adverse RSV vaccine reaction, in the 1960s, in which more-severe illness occurred on natural infection after vaccination of infants who were RSV naive and with a formalin-inactivated RSV vaccine. Recent advances in knowledge of the structural biology of the RSV surface fusion glycoprotein, however, have revolutionized RSV vaccine development for preventive interventions and have offered, at last, the hope of an effective and safe vaccine for the prevention of RSV disease. Objective: The purpose of this report was to examine the current evidence that supports the epidemiology, disease manifestations, molecular biology, treatments, and new vaccine development of RSV vaccines. Results: The host-immune response to RSV infection is carried out by two distinct but overlapping universes of mucosal and systemic immune systems in which a balanced set of B- and T-cell responses are involved in protective immunity that includes the mucosal immune system in which immunoglobulin A (IgA) prevails and the systemic immune system in which IgG neutralizing antibody predominates. The key to developing an effective vaccine is now thought to be linked to the availability of a stabilized prefusion F protein in the immunizing vaccine, which can perform a dual function of a balanced mucosal and/or systemic immune response as well as an effective antibody specifically directed to critical epitopes on the requisite prefusion F protein. Conclusion: The unfortunate manifestation of RSV ERD that occurred in the 1960s has led to a better understanding of the structural biology of the RSV surface fusion glycoprotein and has provided a basis for the development of more effective and safer RSV vaccines and monoclonal antibody preparations for immunoprophylaxis of the dread effects of RSV disease. There are now a large number of clinical trials in progress that are evaluating these products, which include recombinant vector, subunit, particle-based, live-attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. This article gives an overview of the many aspects of RSV disease and development of virus (RSV) vaccines of particular interest to the allergist/immunologist.

Respiratory syncytial virus infection and novel interventions.

The large global burden of respiratory syncytial virus (RSV) respiratory tract infections in young children and older adults has gained increased recognition in recent years. Recent discoveries regarding the neutralization-specific viral epitopes of the pre-fusion RSV glycoprotein have led to a shift from empirical to structure-based design of RSV therapeutics, and controlled human infection model studies have provided early-stage proof of concept for novel RSV monoclonal antibodies, vaccines and antiviral drugs. The world's first vaccines and first monoclonal antibody to prevent RSV among older adults and all infants, respectively, have recently been approved. Large-scale introduction of RSV prophylactics emphasizes the need for active surveillance to understand the global impact of these interventions over time and to timely identify viral mutants that are able to escape novel prophylactics. In this Review, we provide an overview of RSV interventions in clinical development, highlighting global disease burden, seasonality, pathogenesis, and host and viral factors related to RSV immunity.

Respiratory Syncytial Virus Prevention through Monoclonal Antibodies: A Cross-Sectional Study on Knowledge, Attitudes, and Practices of Italian Pediatricians.

Respiratory Syncytial Virus (RSV) is a leading cause of morbidity and hospitalization in all infants. Many RSV vaccines and monoclonal antibodies (mAb) are currently under development to protect all infants, but to date preventive options are available only for preterms. In this study, we assessed the knowledge, attitudes, and practices towards RSV and the preventive use of mAb in a sample of Italian Pediatricians. An internet survey was administered through an internet discussion group, with a response rate of 4.4% over the potential respondents (No. 389 out of 8842, mean age 40.1 ± 9.1 years). The association of individual factors, knowledge, and risk perception status with the attitude towards mAb was initially inquired by means of a chi squared test, and all variables associated with mAb with p < 0.05 were included in a multivariable model calculating correspondent adjusted Odds Ratio (aOR) with 95% confidence intervals (95%CI). Of the participants, 41.9% had managed RSV cases in the previous 5 years, 34.4% had diagnosed RSV cases, and 32.6% required a subsequent hospitalization. However, only 14.4% had previously required mAb as immunoprophylaxis for RSV. Knowledge status was substantially inappropriate (actual estimate 54.0% ± 14.2, potential range 0-100), while the majority of participants acknowledged RSV as a substantial health threat for all infants (84.8%). In multivariable analysis, all these factors were characterized as positive effectors for having prescribed mAb (aOR 6.560, 95%CI 2.904-14.822 for higher knowledge score; aOR 6.579, 95%CI 2.919-14.827 for having a hospital background, and a OR 13.440, 95%CI 3.989; 45.287 for living in Italian Major Islands). In other words, reporting less knowledge gaps, having worked in settings with a higher risk of interaction with more severe cases, and being from Italian Major Islands, were identified as positive effectors for a higher reliance on mAb. However, the significant extent of knowledge gaps highlights the importance of appropriate medical education on RSV, its potential health consequences, and the investigational preventive interventions.

The burden and surveillance of RSV disease in young children in Belgium-expert opinion.

The Belgian population-based RSV surveillance should be improved, and a hospital-led reporting system should be put in place to enable the evaluation of the true burden of RSV disease in Belgium and to improve disease management in the future. • RSV bronchiolitis is a very important cause of infant hospitalization. • The burden of disease in the community is poorly studied and underestimated. • This expert opinion summarizes knowledge gaps and offers insights that allow improvement of local surveillance systems in order to establish a future-proof RSV surveillance system.

A Pan-Pneumovirus vaccine based on immunodominant epitopes of the fusion protein.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two leading causes of severe respiratory infections in children, the elderly, and immunocompromised patients. The fusion (F) protein is the major target of neutralizing antibodies. Recent developments in stabilizing the pre-fusion conformation of the F proteins, and identifying immunodominant epitopes that elicit potent neutralizing antibodies have led to the testing of numerous pre-fusion RSV F-based vaccines in clinical trials. We designed and tested the immunogenicity and protective efficacy of a chimeric fusion protein that contains immunodominant epitopes of RSV F and hMPV F (RHMS-1). RHMS-1 has several advantages over vaccination with pre-fusion RSV F or hMPV F, including a focus on recalling B cells to the most important protective epitopes and the ability to induce protection against two viruses with a single antigen. RHMS-1 was generated as a trimeric recombinant protein, and analysis by negative-stain electron microscopy demonstrated the protein resembles the pre-fusion conformation. Probing of RHMS-1 antigenicity using a panel of RSV and hMPV F-specific monoclonal antibodies (mAbs) revealed the protein retains features of both viruses, including the pre-fusion site Ø epitope of RSV F. Mice immunized with RHMS-1 generated neutralizing antibodies to both viruses and were completely protected from RSV or hMPV challenge. Overall, this study demonstrates protection against two viruses with a single antigen and supports testing of RHMS-1 in additional pre-clinical animal models.

WHO preferred product characteristics for monoclonal antibodies for passive immunization against respiratory syncytial virus (RSV) disease in infants – Key considerations for global use

World Health Organization (WHO) preferred product characteristics describe preferences for product attributes that would help optimize value and use to address global public health needs, with a particular focus on low- and middle-income countries. Having previously published preferred product characteristics for both maternal and paediatric respiratory syncytial virus (RSV) vaccines, WHO recently published preferred product characteristics for monoclonal antibodies to prevent severe RSV disease in infants. This article summarizes the key attributes from the preferred product characteristics and discusses key considerations for future access and use of preventive RSV monoclonal antibodies.

Bringing Preventive RSV Monoclonal Antibodies to Infants in Low- and Middle-Income Countries: Challenges and Opportunities.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) in infants. Most deaths occur in infants under 3 months old, and those living in low and middle-income countries (LMICs). There are no maternal or infant RSV vaccines currently approved. An RSV monoclonal antibody (mAb) could fill the gap until vaccines are available. It could also be used when a vaccine is not given, or when there is insufficient time to vaccinate and generate an antibody response. The only currently approved RSV mAb, palivizumab, is too costly and needs monthly administration, which is not possible in LMICs. It is imperative that a safe, effective, and affordable mAb to prevent severe RSV LRTI be developed for infants in LMICs. Next generation, half-life extended mAbs in clinical development, such as nirsevimab, show promise in protecting infants against RSV LRTI. Given that a single dose could cover an entire 5-month season, there is an opportunity to make RSV mAbs affordable for LMICs by investing in improvements in manufacturing efficiency. The challenges of using RSV mAbs in LMICs are the complexities of integrating them into existing healthcare delivery programs and surveillance systems, both of which are needed to define seasonal patterns, and monitor for escape mutants. Collaboration with key stakeholders such as the World Health Organization and Gavi, the Vaccine Alliance, will be essential for achieving this goal.

Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.

A safe and effective mucosal RSV vaccine in mice consisting of RSV phosphoprotein and flagellin variant.

Respiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. The lack of a licensed RSV vaccine calls for the development of vaccines with other targets and vaccination strategies. Here, we construct a recombinant protein, designated P-KFD1, comprising RSV phosphoprotein (P) and the E.-coli-K12-strain-derived flagellin variant KFD1. Intranasal immunization with P-KFD1 inhibits RSV replication in the upper and lower respiratory tract and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+ Tcells provoked by P-KFD1 intranasal (i.n.) immunization either reside in or migrate to the respiratory tract and mediate protection against RSV infection. Single-cell RNA sequencing (scRNA-seq) and carboxyfluorescein succinimidyl ester (CFSE)-labeled cell transfer further characterize the Th1 and Th17 responses induced by P-KFD1. Finally, we find that anti-viral protection depends on either interferon-γ (IFN-γ) or interleukin-17A (IL-17A). Collectively, P-KFD1 is a promising safe and effective mucosal vaccine candidate for the prevention of RSV infection.

Implementation strategies for passive respiratory syncytial virus immunisation

Respiratory syncytial virus (RSV) is one of the last remaining major causes of serious paediatric respiratory infection for which no vaccine or other wide-scale intervention is available. Although an effective prophylactic antibody (palivizumab) has been available for more than two decades, 1 The IMpact-RSV Study GroupPalivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998; 102: 531-537 Crossref Scopus (1716) Google Scholar its effect on the overall disease burden has been modest. The relatively high cost of palivizumab and its narrow indication to only a small proportion of infants who are at high risk of infection 1 The IMpact-RSV Study GroupPalivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998; 102: 531-537 Crossref Scopus (1716) Google Scholar has meant that the majority of infants at high risk from RSV do not receive palivizumab prophylaxis. Collectively, these shortcomings have translated into a large unmet burden of disease that puts millions of infants at risk of serious, life-threatening disease every year. 2 Shi T McAllister DA O'Brien KL et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. 2017; 390: 946-958 Summary Full Text Full Text PDF PubMed Scopus (964) Google Scholar The mortality burden due to RSV is disproportionately borne by children from low-income countries; data from 2010 suggest that more than 99% of RSV-attributable deaths occur in low-income and middle-income countries (LMICs). 3 Nair H Nokes DJ Gessner BD et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010; 375: 1545-1555 Summary Full Text Full Text PDF PubMed Scopus (1823) Google Scholar Respiratory syncytial virus seasonality and prevention strategy planning for passive immunisation of infants in low-income and middle-income countries: a modelling studyIn LMICs with clear RSV seasonality, seasonal approaches to monoclonal antibody and maternal vaccine administration might optimise disease prevention by dose given compared with year-round administration. More data are needed to clarify if seasonal administration of RSV monoclonal antibodies or maternal immunisation is programmatically suitable and cost effective in LMICs. Full-Text PDF Open Access

Postmortem Study of Cause of Death Among Children Hospitalized With Respiratory Illness in Kenya.

In resource-limited settings, acute respiratory infections continue to be the leading cause of death in young children. We conducted postmortem investigations in children <5 years hospitalized with a clinical diagnosis of respiratory disease at Kenya's largest referral hospital. We collected respiratory and other tissues postmortem to examine pathologic processes using histology, molecular and immunohistochemistry assays. Nasopharyngeal, trachea, bronchi and lung specimens were tested using 21-target respiratory pathogen real-time reverse transcription polymerase chain reaction assays deployed on Taqman Array Cards. Expert panels reviewed all findings to determine causes of death and associated pathogens. From 2014 to 2015, we investigated 64 pediatric deaths (median age 7 months). Pneumonia was determined as cause of death in 70% (42/52) of cases where death was associated with an infectious disease process. The main etiologies of pneumonia deaths were respiratory syncytial virus (RSV) (n = 7, 19%), Pneumocystis jirovecii (n = 7, 19%), influenza A (n = 5, 14%) and Streptococcus pneumoniae (n = 5, 14%)-10% of cases had multi-pathogen involvement. Among the other 10 deaths associated with a nonpneumonia infectious process, 4 did not have an etiology assigned, the others were associated with miliary tuberculosis (2), cerebral thrombosis due to HIV (1), Enterobacteriaceae (1), rotavirus (1), and 1 case of respiratory infection with severe hypokalemia associated with RSV. In spite of well-established vaccination programs in Kenya, some deaths were still vaccine preventable. Accelerated development of RSV monoclonal antibodies and vaccines, introduction of seasonal influenza vaccination, and maintenance or improved uptake of existing vaccines can contribute to further reductions in childhood mortality.

The Future of Respiratory Syncytial Virus Disease Prevention and Treatment.

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children, and older or immunocompromised adults. Although aerosolized ribavirin was licensed for RSV treatment on the basis of data demonstrating a reduced need for supplemental oxygen, ribavirin use is limited because of issues with efficacy, safety, and cost. Currently, the treatment of RSV is primarily supportive. New antiviral treatments for RSV are in the early stages of development, but it will be years until any of these may be licensed by the US Food and Drug Administration (FDA). Palivizumab, an RSV monoclonal antibody [immunoprophylaxis (IP)], has demonstrated effectiveness in disease prevention and is the only licensed IP for RSV disease in specific high-risk pediatric populations. Although its efficacy is well established, some challenges that may interfere with its clinical use include cost, need for monthly injections, and changing policy for use by the American Academy of Pediatrics (AAP). Preventing RSV disease would be possible through RSV vaccine development (e.g., live-attenuated, vector-based subunit, or particle-based). Alternatively, new long-acting monoclonal antibodies have demonstrated promising results in early clinical trials. Despite scientific advances, until new agents become available, palivizumab should continue to be used to reduce RSV disease burden in high-risk patients for whom it is indicated.

Mathematical modelling of respiratory syncytial virus (RSV) in low- and middle-income countries: A systematic review

BackgroundDue to high burden of respiratory syncytial virus (RSV) in low- and middle-income countries (LMIC), international funding organizations have prioritized the development of RSV vaccines. Mathematical models of RSV will play an important role in assessing the relative value of these interventions. Our objectives were to provide an overview of the existing RSV modelling literature in LMIC and summarize available results on population-level effectiveness and cost-effectiveness. MethodsWe searched MEDLINE from 2000 to 2020 for English language publications that employed a mathematical model of RSV calibrated to LMIC. Qualitative data were extracted on study and model characteristics. Quantitative data were collected on key model input assumptions and base case effectiveness and cost-effectiveness estimates for various immunization strategies. FindingsOf the 283 articles reviewed, 15 met inclusion criteria. Ten studies used modelling techniques to explore RSV transmission and/or natural history, while eight studies evaluated RSV vaccines and/or monoclonal antibodies, three of which included cost-effectiveness analyses. Six studies employed deterministic compartmental models, five studies employed individual transmission models, and four studies used different types of cohort models. Nearly every model was calibrated to at least one middle-income country, while four were calibrated to low-income countries. InterpretationThe mathematical modelling literature in LMIC has demonstrated the potential effectiveness of RSV vaccines and monoclonal antibodies. This review has demonstrated the importance of accounting for seasonality, social contact rates, immunity from prior infection and maternal antibody transfer. Future models should consider incorporating individual-level risk factors, subtype-specific effects, long-term sequelae of RSV infections, and out-of-hospital mortality.

Respiratory syncytial virus prophylaxis for prevention of recurrent childhood wheeze and asthma: a systematic review

BackgroundAcute bronchiolitis caused by respiratory syncytial virus (RSV) has been associated with greater risk of recurrent wheezing and asthma. However, it is unclear whether this association is causal. RSV-specific monoclonal antibodies have been shown to reduce RSV-related hospitalisations in high-risk infants, but the longer-term follow-up has given conflicting evidence for prevention of recurrent wheeze or asthma.ObjectiveWe performed a systematic review and meta-analysis to determine whether monoclonal antibody prophylaxis against RSV bronchiolitis reduces the risk of subsequent recurrent wheeze or asthma. If so, this may support the hypothesis of causality.MethodsStudies were identified via an online database search using Embase, MEDLINE, PubMed, Web of Science and the Cochrane Library. Manufacturers of monoclonal antibodies were contacted directly for unpublished data. The intervention of interest was RSV monoclonal antibody prophylaxis, and the primary outcome measure was recurrent wheeze and/or asthma. Studies were screened according to inclusion/exclusion criteria. Included studies were evaluated for quality and assessed for bias independently by 3 reviewers using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) approach. Results were extracted into 2 × 2 outcome tables and a meta-analysis carried out producing forest plots based on relative risk. Heterogeneity was assessed using the I2 statistic.ResultsThe search identified 141 articles, which, after screening, resulted in eight studies (2 randomised controlled trials), thus including 11,195 infants in the meta-analysis. The overall result demonstrated a non-statistically significant reduction in relative risk of developing recurrent wheeze or asthma (RR 0.60; 95% CI 0.31 to 1.16). Study quality was generally low with evidence of publication bias and statistical heterogeneity. However, sub-group analysis excluding studies deemed to be ‘very low’ quality showed a relative risk of 0.42 (95% CI 0.22 to 0.80, p = 0.008). A further sub-group analysis for infants aged 32 to < 36 weeks showed a statistically significant relative risk of 0.35 (95% CI 0.14 to 0.86, p = 0.02).DiscussionWe did not identify an overall statistically significant benefit. However, our two sub-group analyses did find statistically significant benefits of monoclonal antibody therapy on the risk of recurrent wheeze and asthma. The main limitation of this study is the lack of high-quality randomised controlled trials, highlighting the need for more research in this field.

Hospital Admission Trends for Bronchiolitis in Scotland, 2001-2016: A National Retrospective Observational Study.

Bronchiolitis is the commonest cause of respiratory related hospital admissions in young children. This study aimed to describe temporal trends in bronchiolitis admissions for children under 2 years of age in Scotland by patient characteristics, socioeconomic deprivation, and duration of admission. The national hospital admissions database for Scotland was used to extract data on all bronchiolitis admissions (International Classification of Disease, Tenth Revision, code J21) in children <2 years of age from 2001 to 2016. Deprivation quintiles were classified using the 2011 Scottish Index of Multiple Deprivation. Over the 15-year study period, admission rates for children under 2 years old increased 2.20-fold (95% confidence interval [CI], 1.4-3.6-fold) from 17.2 (15.9-18.5) to 37.7 (37.4-38.1) admissions per 1000 children per year. Admissions peaked in infants aged 1 month, and in those born in the 3 months preceding the peak bronchiolitis month-September, October, and November. Admissions from the most-deprived quintile had the highest overall rate of admission, at 40.5 per 1000 children per year (95% CI, 39.5-41.5) compared with the least-deprived quintile, at 23.0 admissions per 1000 children per year (22.1-23.9). The most-deprived quintile had the greatest increase in admissions over time, whereas the least-deprived quintile had the lowest increase. Zero-day admissions, defined as admission and discharge within the same calendar date, increased 5.3-fold (5.1-5.5) over the study period, with the highest increase in patients in the most-deprived quintile. This study provides baseline epidemiological data to aid policy makers in the strategic planning of preventative interventions. With the majority of bronchiolitis caused by respiratory syncytial virus (RSV), and several RSV vaccines and monoclonal antibodies currently in clinical trials, understanding national trends in bronchiolitis admissions is an important proxy for determining potential RSV vaccination strategies.