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

Background Respiratory syncytial virus (RSV) is a leading cause of hospital admission in young children. With several RSV vaccines candidates undergoing clinical trials, recent estimates of RSV burden are required to provide a baseline for vaccine impact studies. Objectives To estimate the number of RSV‐associated hospital admissions in children aged <5 years in England over a 5‐year period from 2007 using ecological time series modelling of national hospital administrative data. Patients/Methods Multiple linear regression modelling of weekly time series of laboratory surveillance data and Hospital Episode Statistics (HES) data was used to estimate the number of hospital admissions due to major respiratory pathogens including RSV in children <5 years of age in England from mid‐2007 to mid‐2012, stratified by age group (<6 months, 6‐11 months, 1‐4 years) and primary diagnosis: bronchiolitis, pneumonia, unspecified lower respiratory tract infection (LRTI), bronchitis and upper respiratory tract infection (URTI). Results On average, 33 561 (95% confidence interval 30 429‐38 489) RSV‐associated hospital admissions in children <5 years of age occurred annually from 2007 to 2012. Average annual admission rates were 35.1 (95% CI: 32.9‐38.9) per 1000 children aged <1 year and 5.31 (95% CI: 4.5‐6.6) per 1000 children aged 1‐4 years. About 84% (95% CI: 81‐91%) of RSV‐associated admissions were for LRTI. The diagnosis‐specific burden of RSV‐associated admissions differed significantly by age group. Conclusions RSV remains a significant cause of hospital admissions in young children in England. Individual‐level analysis of RSV‐associated admissions is required to fully describe the burden by age and risk group and identify optimal prevention strategies.


| BACKGROUND
Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections (RTI) worldwide. 1 In older children and adults, RSV infection often leads to mild upper respiratory tract infection (URTI). However, in infants and young children, RSV is an important cause of severe respiratory infection, particularly bronchiolitis, which may require hospital admission. 2 With a number of RSV vaccine candidates now in phase 2 and 3 clinical trials, it is essential to have accurate estimates of the hospital burden of RSV by age and risk group in order to determine the potential benefits of a future vaccine programme. 3 Calculating the national burden of disease due to RSV is not straightforward. A reliable diagnosis of RSV infection relies on the detection of RSV in respiratory secretions, but only a minority of children hospitalised with an acute respiratory infection will undergo laboratory testing to identify the causal pathogen. 4 The vast majority of respiratory infections are therefore recorded in hospital admission data under non-specific diagnosis such as unspecified pneumonia or bronchiolitis. Hospital admission data alone can therefore not be used to accurately calculate the burden of RSV in secondary care.
Respiratory pathogens have varying temporal patterns which can be observed using laboratory surveillance data. Statistical models which utilise the seasonal variation in laboratory reports by pathogen can be constructed to attribute hospital admissions to different viruses. 4,5 This method of estimating the hospital burden of RSV has previously been used in the UK; however, the most recent study only considers data up to 2009. [4][5][6] Surveillance of respiratory viruses including RSV has been strengthened in England since the 2009 influenza A (H1N1) pandemic, with more widespread use of laboratory confirmation for respiratory viruses with PCR methods, and a greater degree of reporting to national surveillance schemes. 7 In addition, a recent study in the UK demonstrates that hospital admission due to bronchiolitis is increasing over time. 8 These developments emphasise the need for more recent estimates of RSV-associated hospital admissions as previous estimates may not reflect the current burden of disease.

| Hospital Episode Statistics (HES)
The Hospital Episode Statistics (HES) admitted patient care database, held by the Health and Social Care Information Centre (HSCIC), contains routinely collected data on all admissions to all NHS hospitals in England. Records include clinical, geographical and administrative information including admission and discharge dates, on every patient.
In this analysis, an admission refers to a single HES spell-from admission to discharge in one hospital.
Diagnoses are recorded in HES using International Classification of were included in the study. Calendar weeks were defined as blocks of 7 days beginning on 1st January each year, with week 52 allowed to have more than 7 days. Only the primary diagnosis was included to avoid double counting of admissions which may have two or more of these diagnoses. HES data were not available for 2013 onwards. The weekly number of hospital admissions was stratified into three groups: <6 months, 6-11 months and 1-4 years.

| Statistical analysis
In this study, we use the observed temporal variation in weekly laboratory reports of potential causative pathogens to estimate the number of RTI hospital admissions that could be attributed to RSV, building on methods applied in previous modelling studies. 4,10,11 Separate models were developed for each primary diagnosis, using the weekly number of hospital admissions in children <5 years of age in England for each respective diagnosis as the dependent variable. For each diagnosis, separate models were constructed by age group (<6 months, 6-11 months, 1-4 years).
Multiple linear regression models were used to estimate the number of hospital admissions due to RSV from HES data coded as acute bronchiolitis, pneumonia, unspecified LRTI, bronchitis and URTI.
These models have been used in similar studies. 4,10,12,13 All models used the weekly number of laboratory-confirmed episodes in children

| Seasonality of laboratory reports and hospital admissions
The temporal variation in laboratory reports by pathogen is shown in Figure 1 (Table 3). Estimated rates of RSV-associated hospital admissions were, on average, higher in <1-year-olds for all diagnoses except unspecified LRTI, where admission rates in 1-to 4-year-olds were higher (Table 3)     Our study is the first to determine burden of RSV-associated respiratory hospital admissions in children in England according to primary diagnosis and age group. Our study uses smaller age groupings than previous studies to more precisely reflect the differences in RSV-associated illness by age. Our study is also the first to estimate T A B L E 3 Estimated admission rates of RSV-associated hospital admissions per 1000 children <5 y of age in England. T A B L E 2 Total RTI hospital admissions estimated to be due to RSV by the final models, stratified by age group (<6 mo, 6-11 mo, 1-4 y) and primary diagnosis, as a percentage of the total hospital admissions for the respective primary diagnosis