Clinical burden of severe respiratory syncytial virus infection during the first 2 years of life in children born between 2000 and 2011 in Scotland

National data from Scotland (all births from 2000 to 2011) were used to estimate the burden associated with respiratory syncytial virus hospitalisation (RSVH) during the first 2 years of life. RSVHs were identified using the International Classification of Diseases 10th Revision codes. Of 623,770 children, 13,362 (2.1%) had ≥ 1 RSVH by 2 years, with the overall rate being 27.2/1000 (16,946 total RSVHs). Median age at first RSVH was 137 days (interquartile range [IQR] 62–264), with 84.3% of admissions occurring by 1 year. Median length of stay was 2 (IQR 1–4) days and intensive care unit (ICU) admission was required by 4.3% (727) for a median 5 (IQR 2–8) days. RSVHs accounted for 6.9% (5089/73,525) of ICU bed days and 6.2% (64,395/1,033,121) of overall bed days (5370/year). RSVHs represented 8.5% (14,243/168,205) of all admissions between October and March and 14.2% (8470/59,535) between December and January. RSVH incidence ranged from 1.7 to 2.5%/year over the study period. Preterms (RSVH incidence 5.2%), and those with congenital heart disease (10.5%), congenital lung disease (11.2%), Down syndrome (14.8%), cerebral palsy (15.5%), cystic fibrosis (12.6%), and neuromuscular disorders (17.0%) were at increased risk of RSVH. Conclusions: RSV causes a substantial burden on Scottish paediatric services during the winter months. What is known: • Respiratory syncytial virus (RSV) is a leading cause of childhood hospitalisation. What is new: • This 12-year study is the first to estimate the burden of RSV hospitalisation (RSVH) in Scotland and included all live births from 2000 to 2011 and followed > 600,000 children until 2 years old. • The overall RSVH rate was 27.2/1000 children, with 2.1% being hospitalised ≥ 1 times. • RSVHs accounted for 6.2% of all inpatient bed days, which rose to 14.2% during the peak months of the RSV season (December–January), equating to over 1400 hospitalisations and nearly 5500 bed days each year.


Introduction
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections (LRTI) in early childhood, resulting in a substantial burden on health care services, particularly during the colder months (typically October-March) in Northern Hemisphere countries [1][2][3][4][5]. Robust epidemiological data on RSV LRTI aids planning, guides preventive strategies and helps manage healthcare resources effectively. Quantifying the burden of RSV LRTI at a national level can be difficult, due to the limited availability of suitable data sources and a lack of routine testing and confirmatory diagnoses of RSV. Study methodologies have included utilisation of databases of hospital records or medical insurance [3,4] or modelling hospital admissions with national surveillance data [5]. Studies from England have reported RSV hospitalisation (RSVH) rates of 2.4-3.5% in children < 1 year [5,6], rising to 14.3% in those born < 32 weeks' gestational age [wGA] [7]. To our knowledge, no studies reporting such data from Scotland have been published. The Information Services Division (ISD) Scotland collates comprehensive national datasets covering all aspects of hospital care within National Health Service (NHS) Scotland, providing 'linked' data on the total population (> 5 million people) [8]. The aim of this study was to evaluate the hospital burden associated with RSV during the first 2 years of life in children born within NHS Scotland from 2000 to 2011.

Study population
Data on all live births were extracted from the ISD Scottish Maternity and Birth Record dataset (SMR02) for the period 2000-2011 and each child was followed for 2 years. Those who died during the study period for any reason other than RSV-related infection, those whose records were unable to be linked between datasets (SMR02, Scottish Birth Record [SBR], General/Acute Inpatient and Day Case Record [SMR01], and Outpatient Attendance Record [SMR00]), or those who moved away from Scotland were excluded.

Demographic factors
The following demographic factors were assessed: sex, gestational age at birth, birthweight, 5-min Apgar score, need for emergency caesarean, multiple births, mother's age when giving birth, mother's smoking history at pre-delivery assessment (self-declared) and previous pregnancies. Socio-economic status was determined using the Scottish Index of Multiple Deprivation (SIMD) based on the postcode (ZIP code) of the mother, where 1 = most deprived and 5 = least deprived [9].

Identification of RSVHs
RSVHs were defined and analysed as having one of the following three International Classification of Diseases 10th Revision (ICD-10) codes: J12.1 (RSV pneumonia); J20.5 (acute bronchitis due to RSV); or J21.0 (acute bronchiolitis due to RSV) (defined as 'definite' RSV; Table 1). Whilst RSV testing is routinely undertaken in virtually all paediatric inpatient units in Scotland, to provide an estimate of the maximal impact of RSVH, additional ICD-10 codes were analysed covering 'probable' and 'possible' RSVHs. The likelihood of the 'probable' and 'possible' groups being true RSV diagnoses was analysed in two ways. Firstly, these groups were compared to the 'definite' group in terms of seasonality. Secondly, any hospitalisations that occurred out of the RSV season in the 'probable' and 'possible' groups, above the rate in the 'definite' group, were reflected across the whole year and assumed not to be true RSVHs.

Hospital burden of RSV
Details of all RSVHs were captured, including number of children admitted and total admissions, average length of stay (LOS), number of bed days and requirement for admission to an intensive care unit (ICU). RSVH rates (per 1000 children), the seasonality of RSV burden (defined as October-March) and the incidence of RSVH in preterms (≤ 36 wGA) and other recognised high-risk groups, including those with congenital heart disease (CHD)/pulmonary hypertension (PH), congenital lung disease (CLD)/bronchopulmonary dysplasia (BPD), Down syndrome, cystic fibrosis, cerebral palsy and neuromuscular disorders (identified using ICD-10 codes; Table 1), were assessed.

Statistical analysis
Chi-squared tests and t tests, as appropriate, were used to assess differences between groups. The Wilson method was used to calculate 95% confidence intervals for incidence rates. Analysis of RSVHs over time was via linear regression and ANOVA. RSVHs by month of birth were compared by chi-squared test. All analyses were performed using StatsDirect version 2.8.0, SPSS for Windows version 15.0, and Microsoft Excel.

Maximal burden of RSVH
Differing methodologies, data sources, populations and RSVH definitions complicate comparisons between studies. In general, earlier studies (1990s to early 2000s) have tended to report lower RSVH rates than those conducted in the last decade [5,6,13,[15][16][17][18]. One study of 15,116 children < 2 years reported a RSVH rate of 16.3/1000 between 1996 and 1999, based on a positive immunofluorescence test [6]. This is just over half the rate found in our study (27.2/1000), albeit this rate was calculated over 2 years so it is not directly comparable. The average LOS (ours: median 2 days vs. median 2 days [6]) and admission to ICU (4.3% vs. 2.7% [6]) in both studies, however, were broadly similar.
Our study provides further evidence for several high-risk groups and known risk factors for RSVH, including birth in proximity to the RSV season, maternal smoking, low social class/deprivation, male sex, siblings in the household, and multiple births [19][20][21]. Children born prematurely were found to be at increased risk of RSVH, including those born moderate-late preterm (33-35 wGA), where the incidence was more than double that in term children (4.6% vs. 1.9%, respectively; p < 0.0001). These data support the case for preventive strategies against severe RSV infection in preterm infants [22][23][24]. In addition to established high-risk comorbidities, such as CLD/BPD and CHD, our study provides valuable new data on the increased risk of RSVH in children with Down syndrome (RSVH incidence: 14.8%), cystic fibrosis (12.6%), cerebral palsy (15.5%), and neuromuscular disorders (17.0%), where published data are more scarce [25].
The primary analysis in this paper focussed on the RSV diagnoses J12.1, J20.5 and J21.0 and, with RSV testing routine in almost all paediatric inpatient units in Scotland, this is likely to provide a robust estimate of the burden of RSVH in Scotland. However, it is acknowledged that this approach has certain limitations in that it relies on coding precision and   Table 1 for full group definitions might, therefore, underestimate the true burden of RSVH. By including additional ICD-10 codes for 'probable' and 'possible' RSV cases, as has been done in other studies [2,5], it was estimated that the maximal rate of RSVH was 45.9/1000. Another limitation is that there is no method to identify through the ISD databases those children that received palivizumab prophylaxis, although during the time period palivizumab use was restricted on a case-by-case basis to infants < 12 months with extreme prematurity, acyanotic CHD, congenital or acquired significant lung diseases, and immunodeficiency [26]; hence, the impact on overall rates would have been minimal. This study, which covered all live births from 2000 to 2011, provides a reliable estimate of the significant and rising burden of RSVH in young children (< 2 years) in Scotland. These data can aid the planning and delivery of preventive strategies and care and highlight the need for the development of an effective vaccine.
Authors' contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by SB and BRG and all authors commented on this and subsequent versions of the manuscript. All authors read and approved the final manuscript.
Funding Financial support for this study was provided by AbbVie.

Compliance with ethical standards
Conflict of interest JC and RT have received research funding and/or compensation as advisor/lecturer from AbbVie. SB, BRG and JF are employees of Strategen. Strategen has received consultancy and research fees from AbbVie for work on this and other projects. CM is an employee of ISD Scotland. ISD Scotland has received research fees from AbbVie for data analysis work on this project. EG is an employee of AbbVie and holds stock in AbbVie.
Ethical approval The UK National Research Ethic Service confirmed that ethical approval was not required and the ISD Privacy Advisory Committee gave their approval for the study. All data were accessed and analysed using the ISD 'Safe Haven' system to ensure anonymity, confidentiality, and security.
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