Burden of hospital admissions caused by respiratory syncytial virus (RSV) in infants in England: A data linkage modelling study

doi:10.1016/j.jinf.2019.02.012

Journal of Infection

Volume 78, Issue 6, June 2019, Pages 468-475

https://doi.org/10.1016/j.jinf.2019.02.012 Get rights and content

Highlights

•
Novel methodology using linked data to estimate the hospital burden of RSV.
•
Detailed estimates of RSV-associated admissions and bed days in infants in England.
•
RSV-associated admissions peaked in infants aged 6 weeks.
•
RSV-associated admissions peaked in infants born September to November.

Summary

Objectives

Current national estimates of respiratory syncytial virus (RSV)-associated hospital admissions are insufficiently detailed to determine optimal vaccination strategies for RSV. We employ novel methodology to estimate the burden of RSV-associated hospital admissions in infants in England, with detailed stratification by patient and clinical characteristics.

Methods

We used linked, routinely collected laboratory and hospital data to identify laboratory-confirmed RSV-positive and RSV-negative respiratory hospital admissions in infants in England, then generate a predictive logistic regression model for RSV-associated admissions. We applied this model to all respiratory hospital admissions in infants in England, to estimate the national burden of RSV-associated admissions by calendar week, age in weeks and months, clinical risk group and birth month.

Results

We estimated an annual average of 20,359 (95% CI 19,236-22,028) RSV-associated admissions in infants in England from mid-2010 to mid-2012. These admissions accounted for 57,907 (95% CI 55,391-61,637) annual bed days. 55% of RSV-associated bed days and 45% of RSV-associated admissions were in infants <3 months old. RSV-associated admissions peaked in infants aged 6 weeks, and those born September to November.

Conclusions

We employed novel methodology using linked datasets to produce detailed estimates of RSV-associated admissions in infants. Our results provide essential baseline epidemiological data to inform future vaccine policy.

Introduction

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness in young children worldwide, and a major cause of hospital admission in UK infants.1, 2, 3, 4 The majority of the burden of RSV-associated hospital admissions is accounted for by infants less than six months old, particularly those born around the beginning of the RSV season.4, 5 Promising vaccine candidates are now in Phase 2 and 3 clinical trials,6, 7 with several potential future vaccination strategies being considered. These include maternal immunisation to protect neonates, immunisation of very young infants prior to exposure, or a live vaccine targeted to older infants and young children (with the aim of also providing indirect protection to very young infants).⁸ However, further information on the burden of RSV-associated admissions according to age and underlying chronic conditions is required to determine the optimal target populations for a potential future vaccine.⁹

Currently available methods of estimating the burden of RSV-associated hospital admissions are not sufficiently detailed to determine optimal vaccination strategies for RSV. Only a minority of hospitalised children presenting with acute respiratory infection undergo laboratory testing to identify the causal pathogen,⁴ so previous studies of the national burden of RSV have either: (a) relied on clinical coding of bronchiolitis in hospital admission databases as a proxy for RSV-associated hospital admissions, or (b) used time-series modelling methods which utilise the seasonality of RSV and other major respiratory viruses to infer the burden of RSV-associated hospital admissions.⁴^,10, 11, 12 Neither of these approaches are ideal. Not all bronchiolitis admissions are due to RSV, and while estimates based on time series modelling can be stratified by some key characteristics such as age group and diagnosis,⁴ they are derived from models based on aggregate data using an ecological study design (inferring causality from the temporal association of the hospital admission and laboratory data). Therefore, outcomes from time series models are limited in the detail they provide, and both approaches are subject to bias.

In this study, we use linked, routinely collected laboratory surveillance and hospital admissions data and employed a novel predictive model to estimate the national burden of RSV-associated hospital admissions in infants in England from mid-2010 to mid-2012. Using this individual-level data, we estimate both the number and rate of RSV-associated hospital admissions and the number of RSV-associated bed days, with detailed stratification by sex, age in weeks and months, clinical risk group and month of birth for the first time.

Section snippets

Hospital Episode Statistics (HES)

We used the Hospital Episode Statistics (HES) Admitted Patient Care database, held by National Health Service (NHS) Digital. It contains routinely collected data on all admissions to all National Health Service (NHS) hospitals in England.¹³ Healthcare is free at the point of use in the NHS, and 99% of hospital activity in England takes place in NHS hospitals. Diagnoses are recorded using International Classification of Diseases 10th Revision (ICD- 10) codes, with up to 20 diagnosis codes

Overview of linked dataset

We included data from 24 out of 179 potential NHS trusts contributing data to HES within the study period (with at least 50 linked RDS records over the study period, and which tested >10% of their total respiratory admissions across the study period), representing 80% of the total RDS-HES linked admissions. There were a total of 6758 linked admissions in infants <1 year old during the study period, with 44% (2947 admissions) positive for RSV. 49% (1445 admissions) of RSV-positive linked

Discussion

Our study is the first to use linked routinely collected laboratory and hospital records to estimate the national secondary care burden of RSV in infants. Using our linked dataset which included both RSV-positive and RSV-negative admissions, we estimate a total annual average of 20,359 (95% CI 19,236-22,028) RSV-associated admissions in infants younger than 1 year of age in England during the two-year period from mid-2010 to mid-2012. These admissions accounted for approximately 57,907 (95% CI

Conflict of interest

The authors have no conflicts of interest to disclose.

Author contributions

RMR, PH and RP designed the study. NP and MM carried out the data linkage. RMR was responsible for data analysis and drafted the manuscript. RMR, PH, RP and FW contributed to data analysis methodology and interpretation. All authors reviewed and edited the final manuscript.

Role of the funding source

The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Funding

Farr Institute of Health Informatics Research (grant MR/K006584/1). Research at UCL Great Ormond Street Institute of Child Health is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre.

References (25)

H. Nair 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)
T. Shi 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)
R.J. Pitman et al.
Assessing the burden of influenza and other respiratory infections in England and Wales
J Infect
(2007)
D. Cromer et al.
The burden of influenza in England by age and clinical risk group: a statistical analysis to inform vaccine policy
J Infect
(2014)
D. Cromer et al.
Burden of paediatric respiratory syncytial virus disease and potential effect of different immunisation strategies: a modelling and cost-effectiveness analysis for England
Lancet Public Heal
(2017)
C.B. Hall et al.
The burden of respiratory syncytial virus infection in young children
N Engl J Med
(2009)
R.M. Reeves et al.
Estimating the burden of respiratory syncytial virus (RSV) on respiratory hospital admissions in children less than five years of age in England, 2007-2012
Influenza Other Respi Viruses
(2017)
R.M. Reeves et al.
Epidemiology of laboratory-confirmed respiratory syncytial virus infection in young children in England, 2010–2014: the importance of birth month
Epidemiol Infect
(2016)
J. Murray et al.
Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals
Arch Dis Child
(2014)
PATH. RSV Vaccine Snapshot - PATH Vaccine Resource Library [Internet]. 2017....

P.A. Jorquera et al.

Understanding respiratory syncytial virus (RSV) vaccine development and aspects of disease pathogenesis

Expert Rev Vaccines

(2016)

H. Campbell et al.

Respiratory syncytial virus (RSV) disease - new data needed to guide future policy

J Glob Health

(2015)

Cited by (34)

Differential anti-viral response to respiratory syncytial virus A in preterm and term infants
2024, eBioMedicine
Preterm infants are more likely to experience severe respiratory syncytial virus (RSV) disease compared to term infants. The reasons for this are multi-factorial, however their immature immune system is believed to be a major contributing factor.
We collected cord blood from 25 preterm (gestational age 30.4–34.1 weeks) and 25 term infants (gestation age 37–40 weeks) and compared the response of cord blood mononuclear cells (CBMCs) to RSVA and RSVB stimulation using neutralising assays, high-dimensional flow cytometry, multiplex cytokine assays and RNA-sequencing.
We found that preterm and term infants had similar maternally derived neutralising antibody titres to RSVA and RSVB. Preterm infants had significantly higher myeloid dendritic cells (mDC) RSV infection compared to term infants. Differential gene expression analysis of RSVA stimulated CBMCs revealed enrichment of genes involved in cytokine production and immune regulatory pathways involving IL-10, IL-36γ, CXCL1, CXCL2, SOCS1 and SOCS3 in term infants, while differentially expressed genes (DEGs) in preterm infants were related to cell cycle (CDK1, TTK, ESCO2, KNL1, CDC25A, MAD2L1) without associated expression of immune response genes. Furthermore, enriched genes in term infants were highly correlated suggesting an increased co-ordination of their immune response to RSVA. When comparing DEGs in preterm and term infants following RSVB stimulation, no differences in immune response genes were identified.
Overall, our data suggests that preterm infants have a more restricted immunological response to RSVA compared with term infants. While further studies are required, these findings may help to explain why preterm infants are more susceptible to severe RSV disease and identify potential therapeutic targets to protect these vulnerable infants.
Murdoch Children's Research Institute Infection and Immunity theme grant.
Comparison of a static cohort model and dynamic transmission model for respiratory syncytial virus intervention programs for infants in England and Wales
2024, Vaccine
A recent study comparing results of multiple cost-effectiveness analyses (CEAs) in a hypothetical population found that monoclonal antibody (mAb) immunoprophylaxis for respiratory syncytial virus (RSV) in infants averted fewer medically attended cases when estimated using dynamic transmission models (DTMs) versus static cohort models (SCMs). We aimed to investigate whether model calibration or parameterization could be the primary driver of inconsistencies between SCM and DTM predictions.
A recently published DTM evaluating the CEA of infant mAb immunoprophylaxis in England and Wales (EW) was selected as the reference model. We adapted our previously published SCM for US infants to EW by utilizing the same data sources used by the DTM. Both models parameterized mAb efficacy from a randomized clinical trial (RCT) that estimated an average efficacy of 74.5% against all medically attended RSV episodes and 62.1% against RSV hospitalizations. To align model assumptions, we modified the SCM to incorporate waning efficacy. Since the estimated indirect effects from the DTM were small (i.e., approximately 100-fold smaller in magnitude than direct effects), we hypothesized that alignment of model parameters should result in alignment of model predictions. Outputs for model comparison comprised averted hospitalizations and averted GP visits, estimated for seasonal (S) and seasonal-with-catchup (SC) immunization strategies.
When we aligned the SCM intervention parameters to DTM intervention parameters, significantly more averted hospitalizations were predicted by the SCM (S: 32.3%; SC: 51.3%) than the DTM (S: 17.8%; SC: 28.6%). The SCM most closely replicated the DTM results when the initial efficacy of the mAb intervention was 62.1%, leading to an average efficacy of 39.3%. Under this parameterization the SCM predicted 17.4% (S) and 27.7% (SC) averted hospitalizations. Results were similar for averted GP visits.
Parameterization of the RSV mAb intervention efficacy is a plausible primary driver of differences between SCM versus DTM model predictions.
Optimal Respiratory Syncytial Virus intervention programmes using Nirsevimab in England and Wales
2022, Vaccine
Citation Excerpt :
The results of the MELODY trial, a phase II/III randomised control trial assessing the safety and tolerability of Nirsevimab, suggest a higher efficacy against hospitalisation (62% vs. 55%) and a longer duration of protection (∼150 days vs 30 days) than Palivizumab [4,9,10]. The prospect of a more effective prophylactic against RSV, which is expected to be cheaper than a single dose of Palivizimab [11], could broaden access to RSV prevention from only high-risk neonates to healthy infants who also have a large burden of RSV disease [12]. The Joint Committee on Vaccination and Immunisation (JCVI) in the UK has emphasised that modelling should be used to explore the impact of expanding the eligibility criteria for RSV immunisation with this new monoclonal antibody [13].
Respiratory Syncytial Virus (RSV) is a major cause of acute lower respiratory tract infections (ALRI) in infants. There are no licensed vaccines and only one monoclonal antibody available to protect infants from disease. A new and potentially longer-lasting monoclonal antibody, Nirsevimab, showed promising results in phase IIb/III trials. We evaluate the cost-effectiveness of Nirsevimab intervention programmes in England and Wales.
We used a dynamic model for RSV transmission, calibrated to data from England and Wales. We considered a suite of potential Nirsevimab programmes, including administration to all neonates (year-round); only neonates born during the RSV season (seasonal); or neonates born during the RSV season plus infants less than six months old before the start of the RSV season (seasonal + catch-up).
If administered seasonally to all infants at birth, we found that Nirsevimab would have to be priced at £63 or less per dose for at least 50% certainty that it could cost-effectively replace the current Palivizumab programme, using an ICER threshold of £20,000/QALY. An extended seasonal programme which includes a pre-season catch-up becomes the optimal strategy at a purchasing price of £32/dose or less for at least 50% certainty. At a purchasing price per dose of £5-32, the annual implementation costs of a seasonal programme could be as high as £2 million before a switch to a year-round strategy would be optimal.
Nirsevimab has the potential to be cost-effective in England and Wales not only for use in high-risk infants.
Determinants of RSV epidemiology following suppression through pandemic contact restrictions
2022, Epidemics
Citation Excerpt :
Hospitalisation rates (per 100,000 population) were also available for the period following the emergence of COVID-19. While less severe than for case notifications, there is some level of under-ascertainment in the hospitalisation data, which we accounted for by taking the ratio of annual hospitalisations in SARI-Watch to estimates of the full RSV-associated annual hospitalisation burden in the literature (Taylor et al., 2016; Reeves et al., 2017, 2019; Fleming et al., 2015; Sharp et al., 2021). The risk for hospitalisation upon infection was modelled specific to the age groups based on estimates from previous model fitting (Hodgson et al., 2020).
COVID-19 related non-pharmaceutical interventions (NPIs) led to a suppression of RSV circulation in winter 2020/21 in the UK and an off-season resurgence in Summer 2021. We explore how the parameters of RSV epidemiology shape the size and dynamics of post-suppression resurgence and what we can learn about them from the resurgence patterns observed so far.
We developed an age-structured dynamic transmission model of RSV and sampled the parameters governing RSV seasonality, infection susceptibility and post-infection immunity, retaining simulations fitting the UK’s pre-pandemic epidemiology by a set of global criteria consistent with likelihood calculations. From Spring 2020 to Summer 2021 we assumed a reduced contact frequency, returning to pre-pandemic levels from Spring 2021. We simulated transmission forwards until 2023 and evaluated the impact of the sampled parameters on the projected trajectories of RSV hospitalisations and compared these to the observed resurgence.
Simulations replicated an out-of-season resurgence of RSV in 2021. If unmitigated, paediatric RSV hospitalisation incidence in the 2021/22 season was projected to increase by 30–60% compared to pre-pandemic levels. The increase was larger if infection risk was primarily determined by immunity acquired from previous exposure rather than age-dependent factors, exceeding 90 % and 130 % in 1–2 and 2–5 year old children, respectively. Analysing the simulations replicating the observed early outbreak in 2021 in addition to pre-pandemic RSV data, we found they were characterised by weaker seasonal forcing, stronger age-dependence of infection susceptibility and higher baseline transmissibility.
COVID-19 mitigation measures in the UK stopped RSV circulation in the 2020/21 season and generated immunity debt leading to an early off-season RSV epidemic in 2021. A stronger dependence of infection susceptibility on immunity from previous exposure increases the size of the resurgent season. The early onset of the RSV resurgence in 2021, its marginally increased size relative to previous seasons and its decline by January 2022 suggest a stronger dependence of infection susceptibility on age-related factors, as well as a weaker effect of seasonality and a higher baseline transmissibility. The pattern of resurgence has been complicated by contact levels still not back to pre-pandemic levels. Further fitting of RSV resurgence in multiple countries incorporating data on contact patterns will be needed to further narrow down these parameters and to better predict the pathogen’s future trajectory, planning for a potential expansion of new immunisation products against RSV in the coming years.
The chest X-ray in acute bronchiolitis: Technical quality, findings, and an assessment of its reliability
2021, Anales de Pediatria
A pesar de las recomendaciones de las actuales Guías de Práctica Clínica, la radiografía de tórax sigue siendo una prueba diagnóstica ampliamente utilizada en la evaluación de lactantes con bronquiolitis aguda (BA). No obstante, su reproductibilidad en estos pacientes no ha sido muy estudiada. En la presente investigación, se evalúan radiografías describiéndose su calidad técnica, hallazgos radiológicos en las mismas y se aportan nuevas evidencias sobre la concordancia entre observadores.
Sobre un total de 281 lactantes ingresados por bronquiolitis aguda, se realizaron 140 radiografías de tórax. Se evaluó la presencia o ausencia de 10 signos radiográficos previamente consensuados por 12 médicos de diferentes especialidades. El nivel de concordancia entre dos observadores y en grupos de tres o más, fue estudiado mediante el índice kappa de Cohen y de Fleiss, respectivamente.
Únicamente en el 8,5% de las radiografías se evidenciaron signos de BA complicada. La concordancia entre observadores en grupos de tres o más fue mediana y con escasa variabilidad (kappa: 0,20-0,40), sin embargo, entre dos observadores, cada médico observador frente al radiólogo de referencia, la variabilidad fue más amplia, (kappa: –0,20-0,60). Este nivel de concordancia se relacionaba con factores tales como el signo a evaluar, la especialidad médica y el grado de experiencia profesional, entre otros.
Los bajos niveles de concordancia entre observadores y su amplia variabilidad, convierten a la radiografía de tórax en una herramienta diagnóstica poco fiable y no recomendable para la evaluación de lactantes con BA.
Despite the recommendations of the current Clinical Practice Guidelines, the chest x-ray continues to be a widely used diagnostic test in the assessment of infants with acute bronchiolitis (AB). However, there have not been many studies that have assessed its reproducibility in these patients. In the present study, an evaluation is made on the radiographs, describing their quality, their radiological findings, and provides new evidence on the agreement between observers.
Out of a total of 281 infants admitted due to acute bronchiolitis, 140 chest x-rays were performed. Twelve doctors from different specialities evaluated the presence or absence of 10 radiological signs previously agreed by consensus. The level of agreement between 2 observers, and in groups of 3 or more, were analysed using the Cohen and Fleiss kappa index, respectively.
Only 8.5% of the radiographs showed evidence of a complicated AB. The between-observer agreement in groups of 3 or more was medium, and with little variability (kappa: 0.20-0.40). However, between 2 observers, each observer against radiologist, the variability was wider, (kappa: –0.20-0.60). This level of agreement was associated with factors including, the sign to evaluate, the medical specialty, and level of professional experience.
The low levels of agreement between observers and the wide variability, makes the chest x-ray an unreliable diagnostic tool, and is not recommended for the assessment of infants with AB.
Compromised SARS-CoV-2-specific placental antibody transfer
2021, Cell
Citation Excerpt :
Although up to 16% of pregnant women test positive for SARS-CoV-2 in geographic hotspots (Breslin et al., 2020; Sutton et al., 2020), pregnant women and neonates are excluded from vaccine and therapeutic trials due to enhanced safety standards required for this population. Previous work has shown that both newborns and pregnant women are particularly susceptible to respiratory infections, including influenza and respiratory syncytial virus (RSV) (Zaman et al., 2008; Rasmussen et al., 2012; Gerretsen and Sande, 2017; Reeves et al., 2019; Liu et al., 2020). Recent data demonstrate that a greater proportion of neonates and infants have severe or critical illness upon SARS-CoV-2 infection compared to older pediatric counterparts (Kim et al., 2020; Dong et al., 2020).
SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.

View all citing articles on Scopus

View full text

Burden of hospital admissions caused by respiratory syncytial virus (RSV) in infants in England: A data linkage modelling study

Highlights

Summary

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Hospital Episode Statistics (HES)

Overview of linked dataset

Discussion

Conflict of interest

Author contributions

Role of the funding source

Funding

Lancet

Lancet

J Infect

J Infect

Lancet Public Heal

The burden of respiratory syncytial virus infection in young children

N Engl J Med

Estimating the burden of respiratory syncytial virus (RSV) on respiratory hospital admissions in children less than five years of age in England, 2007-2012

Influenza Other Respi Viruses

Epidemiology of laboratory-confirmed respiratory syncytial virus infection in young children in England, 2010–2014: the importance of birth month

Epidemiol Infect

Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals

Arch Dis Child

Understanding respiratory syncytial virus (RSV) vaccine development and aspects of disease pathogenesis

Expert Rev Vaccines

Respiratory syncytial virus (RSV) disease - new data needed to guide future policy

J Glob Health