Preschool respiratory hospital admissions following infant bronchiolitis: a birth cohort study.

Authors: Dr Helen Skirrow1, Dr Thomas Wincott2, Dr Elizabeth Cecil3, Dr Alex Bottle4, Dr Ceire Costelloe5 and Prof Sonia Saxena6.

Author affiliations:

1Corresponding author.Speciality Registrar, London Public Health Medicine Specialist Training Program. Honorary Clinical Research Fellow, School of Public Health, Imperial College London. Email:h.skirrow@imperial.ac.uk. Phone: 07947439518.

2GP Registrar, School of Public Health, Imperial College London.

3Research Associate, School of Public Health, Imperial College London.

4 Reader in Medical Statistics, Dr Foster Unit, Department of Medicine. School of Public Health, Imperial College London.

5 Non-clinical Senior Lecturer and NIHR career development fellow, School of Public Health, Imperial College London.

6Professor of Primary Care, School of Public Health, Imperial College London.

Contributors: HS contributed to the interpretation of the data, drafted the article, revised it critically and prepared the final version to be published with input from senior author, SS. TW, EC and SS contributed to the conception and design, acquisition of data and analyses and interpretation of the data. SS, TW, EC, AB and CC reviewed the drafted manuscript critically for important intellectual content and gave HS approval of the final version to be published.

Funding: SS and Imperial College London are grateful for support from the NW London NIHR Collaboration for Leadership in Applied Health Research and Care. CC is supported by a NIHR Career Development fellowship (CDF-2016-09-015).

Competing interests: Dr. Skirrow reports personal fees from StGilesMedical, outside the submitted work; Dr Wincott and Dr. Cecil have nothing to disclose. Dr. Bottle reports grants from Dr Foster, grants from Medtronic, outside the submitted work; Dr. Costelloe has nothing to disclose. Prof. Saxena reports grants from NIHR career development fellowship, during the conduct of the study;

Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the NIHR, the NHS or the Department of Health.

Word Count: 2500 (excluding title page, abstract, references, figures and tables).

Ethics: Accessing non-identifiable information for secondary use does not require permission from an NHS Research Ethics Committee (REC) according to NHS Health Research

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Authority. However, The Department of Primary Care and Public Health at Imperial College University had permission to hold confidential data for this project from the Data Access Advisory Group (DAAG reference: 310112-b), the predecessor group to Independent Group Advising on the Release of Data under Section 251 of the NHS Act 2006, and approval for use in research was granted from the South East Ethics Research Committee.

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Abstract

Background:  Bronchiolitis causes significant infant morbidity worldwide from hospital

admissions. However, studies quantifying the subsequent respiratory burden in children under

5 years are lacking.

Objective: To estimate the risk of subsequent respiratory hospital admissions in children

under 5 years in England following bronchiolitis admission in infancy.

Design: Retrospective population-based birth cohort study.

Setting: Public hospitals in England.

Patients: We constructed a birth cohort of 613,377 infants born between 1.4.2007 and

31.3.2008, followed up until aged 5 years by linking Hospital Episode Statistics (HES)

admissions data.

Methods: We compared the risk of respiratory hospital admission due to asthma, wheezing

and lower and upper respiratory tract infections(LRTI & URTI) in infants who had been

admitted for bronchiolitis with those who had not, using Cox proportional hazard regression.

We adjusted hazard ratios for known respiratory illness risk factors including living in

deprived households, being born preterm or with a comorbid condition.

Results: We identified 16,288/613,377 infants(2.7 %) with at least one admission for

bronchiolitis. Of these, 21.7% had a further respiratory hospital admission by age 5 years

compared with 8% without a previous bronchiolitis admission, (HR(adjusted),2.82, 95%CI

2.72-2.92). The association was greatest for asthma (HR(adjusted), 4.35, 95%CI 4.00-4.73)

and wheezing admissions (HR(adjusted), 5.02, 95%CI 4.64-5.44) but were also significant

for URTI and LRTI admissions.

Conclusions: Hospital admission for bronchiolitis in infancy is associated with a 3-to-5-fold

risk of subsequent respiratory hospital admissions from asthma, wheezing and respiratory

infections. One in five infants with bronchiolitis hospital admissions will have a subsequent

respiratory hospital admission by age 5 years.

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What is already known on this topic:

Bronchiolitis is responsible for significant childhood morbidity and health service

burden.

Bronchiolitis in infancy is also associated with subsequent childhood respiratory

illnesses such as wheezing and asthma.

What this study adds:

This large population-based birth cohort record linkage study confirms that

bronchiolitis is associated with a 3-5 fold increased risk of subsequent severe

childhood respiratory illness.

One in five children with an infant bronchiolitis hospital admission will be admitted

again for a respiratory illness such as asthma, wheezing or respiratory infections.

Over 2000 childhood respiratory hospital admissions between 1-4 years are estimated

to be attributed to a previous infant bronchiolitis admission even after adjustment for

known risk factors.

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Introduction

Respiratory Syncytial Virus(RSV) is responsible for significant infant morbidity and

mortality worldwide(1–3). Recent estimates suggest globally 3·2 million hospital admissions

occur yearly for acute RSV lower respiratory infections in children under 5 years, with 45%

in infants under 6 months(1). Low and Middle Income Countries(LMIC) experience a higher

burden of RSV associated childhood respiratory infections, though less data is available(1).

Bronchiolitis is estimated to be caused by RSV in around 75% of cases(4). In the

United Kingdom(UK) bronchiolitis is normally managed in the community with supportive

treatment(5,6). However, an estimated 2.4-4.6% of cases require hospital admission(7–9).

Bronchiolitis hospital admissions impact heavily on acute hospital services(2,9,10),

especially during peak winter seasons. High risk infants are eligible for RSV prophylaxis

using the monoclonal antibody, Palivizumab and several vaccines are in development that

may change the RSV worldwide population burden(11).

To date, studies reporting bronchiolitis hospital admissions have focused on acute

hospitalisations(7,8). In England an association between bronchiolitis admissions in infancy

and subsequent childhood asthma hospital admissions has been reported but did not establish

a temporal relationship(9). The association between infant RSV infection and subsequent

childhood respiratory health is not yet fully understood(12). Most studies examining this

relationship have been smaller case-control or regional cohort studies, subject to reporting

bias with variable follow-up periods(12–16). A cohort study in North America found infant

RSV infection was associated with increased risk of recurrent wheeze after following 70,000

infants until age 5 years, of whom 1.74% had infant RSV(17). A smaller English birth cohort

study found infant bronchiolitis admission with laboratory confirmed RSV infection was

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associated with subsequent wheeze and asthma however only followed up 96 children by

30-42 months of age(14).

Hence, large population studies accurately quantifying subsequent respiratory hospital

admissions following bronchiolitis admissions are currently lacking. Improvements in

hospital data quality(18) have enabled us to link electronically coded clinical records to study

almost the entire English birth cohort over several years. The aim of this study was to

estimate the subsequent risk of severe childhood respiratory illness following an infant

bronchiolitis admission.

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Methods

Data Source

We performed a retrospective cohort study using the national administrative database

of all admissions to National Health Service(NHS) hospitals in England, known as the

Hospital Episode Statistics(HES) database(7,18). HES covers all admissions to NHS

hospitals, including hospital births(18,19). Admission diagnoses are coded using the

International Classification of Diseases 10th Revision,(ICD-10).

Study Population

Our study population consisted of all infants born in and discharged from an NHS

hospital in England between 1st April 2007 and 31st March 2008, extracted from the HES

database(7). We used unique identifiers to link an individual’s birth records in HES to their

subsequent emergency admission records up to the child’s fifth birthday. The birth cohort

was linked by deterministic linkage based on unique HES ID to unplanned (emergency)

admission data(18). An unplanned emergency admission refers to an event that is

unexpected, when a child presents acutely and is referred immediately for hospital

treatment(20). Previous work has reported on the use of individual birth records linked to

other healthcare records as a source of longitudinal, population level data(18).

Children were considered to have had bronchiolitis if they had an admission for

bronchiolitis coded in the primary diagnosis field in the first year of life (see appendix for

ICD-10 codes). We did not include children admitted with bronchiolitis after 1 year of age in

the exposure group (n=1,677) owing to the diagnostic uncertainty of bronchiolitis in children

older than 1 year. We excluded all elective admissions and 356 children who died in hospital

within the follow-up period.

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Outcomes and confounding variables

Our primary outcome was emergency admission for acute respiratory illness between

1 and ≤5 years. As we were interested in the risk for subsequent admission following

exposure to bronchiolitis, we excluded emergency respiratory admissions before 1 year.

Admissions for acute respiratory illness were defined using ICD-10 codes for asthma

wheezing, LRTI and URTI, (see appendix).

In addition, we extracted data on prematurity or low birth weight, comorbidities at

birth, Index of Multiple Deprivation (IMD, 2015), gender and ethnicity. IMD was based on

area of residence recorded in the HES birth record and used as a marker of deprivation(21).

Infants were categorised as having a comorbidity based on information recorded in individual

HES birth records and then information from any subsequent hospital admission records from

the study year. This included known risk factors associated with RSV used in previous

work(7). Infants included in the co-morbidity category were those with the following

diagnoses: Immunodeficiencies, Cystic Fibrosis, Chronic Lung Disease, Congenital Heart

Disease, Nervous system congenital anomalies, other congenital anomalies, Down’s

Syndrome and Cerebral Palsy (see appendix for full ICD codes).

Prematurity or LBW was derived from all recorded diagnoses at birth using ICD

codes associated with disorders related to short gestation and low birth weight (see appendix

for full ICD codes).

Statistical Analyses

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We calculated the difference in proportion of children with subsequent respiratory

admissions between 1 and 5 years between those with or without bronchiolitis admissions

under 1 year. We calculated hazard ratios for acute respiratory admission for children aged 1

to ≤5 years old with and without an infant bronchiolitis admission using Cox’s proportional

regression adjusting for comorbid conditions at birth, prematurity, IMD, ethnicity and gender.

The assumption of proportional hazards was determined by visual inspection of ln-ln plots.

In addition, a sensitivity analysis was performed comparing hazard ratios for acute

respiratory illness for infants using exposure codes for RSV-associated admissions (see

appendix for ICD10 codes).

Population-attributable risk was then calculated for the number of childhood

respiratory admissions up to age 5 years attributable to infant bronchiolitis admissions (see

table 4).

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Results

The birth cohort included 613,377 infants of whom, 16,288 (2.7%) infants had at least

one admission for bronchiolitis in the first year of life. Infants admitted with bronchiolitis

were more likely to be boys (table 1), (unadjusted difference in proportions 7.9%, 95% CI

7.1% - 8.7%) and reside in deprived areas (table 1), compared with infants who were not

admitted. Children born preterm (46,847/613,377, 7.6%) and those born with a comorbid

condition were more likely to have a bronchiolitis admission. Ethnicity was recorded as ‘not

stated’ or ‘not known’ in around 15% of records but analysis found overall ethnicity was

distributed independently of bronchiolitis admissions.

During the follow-up period between 1 and 5 years of age there were 68,315

admissions for respiratory illness. 8% of children had at least one respiratory admission,

(49,509/613,377). Children who had an infant bronchiolitis admission had more subsequent

respiratory admissions (21.7%) overall compared with those who had not (7.6%), (table 2).

The proportion of children with a respiratory admission was significantly greater in those

children who had been admitted with bronchiolitis in infancy compared to those who had not

(absolute difference in proportion 14.1%, 95%CI 13.4-14.7). Preterm infants were 38% more

likely to have a respiratory admission before 5 years old (HR 1.38, 95%CI 1.34-1.42).

Children born with a comorbid condition were 19% more likely to have a respiratory

admission before 5 years of age (HR 1.19, 95%CI 1.16-1.21).

Children who had an infant bronchiolitis admission were overall on average over

twice as likely to be admitted for respiratory admission before the age of 5 years (adjusted

HR 2.8, 95%CI 2.7-2.9) compared with children who did not have a bronchiolitis admission.

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This was similar for RSV-associated disease admission (adjusted hazard ratio 2.95, 95%CI

2.85 - 3.05). Children with a an infant bronchiolitis admission had a fivefold increased risk of

hospital admission for wheezing (HR 5.02, 95%CI 4.64-5.44) and fourfold increased risk of

asthma admission (HR 4.35, 95%CI 4.0-4.73) as well as an increased risk of hospital

admission for LRTI and URTI before their 5th birthday (HRs 3.10, 95%CI 2.91-3.31 and

2.34, 95%CI 2.23-2.45 respectively) after adjusting for sex, deprivation, ethnicity, preterm

birth and being born with a comorbidity (table 3).

We calculated that 2297 additional respiratory hospital admissions between aged 1-5

years are attributable to infant bronchiolitis within our birth cohort(see table 4).

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Discussion

Main Findings

To our knowledge this is the largest population-level study to report an association

between infant bronchiolitis admissions and subsequent childhood respiratory hospital

admissions. More than one in five children (21.7%) who had an infant bronchiolitis

admission had a further respiratory admission by the age of 5 years compared with 8%

without a previous bronchiolitis admission. The association was greatest for asthma and

wheezing admissions, conferring a four to fivefold risk, but was also significant for LRTI and

URTI admissions. We estimated around 2300 additional respiratory admissions are

attributable to a prior bronchiolitis admission in children under 5 years.

Findings in relation to other studies

Our findings are consistent with a number of smaller cohort studies reporting on the

association between bronchiolitis in infancy and childhood wheeze and asthma, as

summarised by the systematic review by Fauroux et al, (2017)(12). Green et al(2015)

reported an association between infant bronchiolitis admission and increased risk for

childhood asthma admissions up to 14 years in England (rate ratio 2.8, 95% CI 2.6– 3.1)(9).

The smaller cohort and use of exposure definitions for bronchiolitis up to 2 years of age

means that confirming a temporal relationship is not possible from this study. Reeves et al

(2017) estimated the UK population hospital admission burden attributable to RSV in

children up to five years but did not include the subsequent respiratory admission burden(8).

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Hence, our study provides the strongest evidence to date of an association between infant

bronchiolitis admission and subsequent respiratory admissions. Quantifying the morbidity

and healthcare burden for infants with severe bronchiolitis requiring admission is important

as bronchiolitis may not be one condition but actually different severity clinical

phenotypes(22).

The pathophysiology behind the relationship between infant RSV and subsequent

respiratory health remains unclear and further work is needed to understand underlying

immune mechanisms. Infant infections may trigger an initial immune response increasing the

likelihood of childhood asthma or a predisposed genetic susceptibility to both infant

respiratory infections and wheeze may be responsible; our study could support either

mechanism. Several immune mediated causal explanations for the association between infant

RSV infections and subsequent development of asthma and wheezing exist(12,23). These

include factors that predispose to wheezing such as genetic susceptibility to bronchial hyper-

reactivity, associated risks such as passive smoke exposure and also viral injury(24,25). An

alternative explanation for the association between infant RSV and subsequent respiratory

health are environmental risk factors such as passive smoking or pollution that could affect

both infant and subsequent admission risk. Additionally, an important explanatory

relationship between infant RSV and subsequent childhood admissions is that clinicians may

lower their threshold for admission if they assess a child who has a previous history of

bronchiolitis admission. National guidance on the management of asthma advises risk

stratification and consideration of previous hospital admissions when deciding on

admission(26).

Strengths & Weaknesses

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Our study strengths include its size and use of nationally representative data that

linked the entire birth cohort of children born in English hospitals to capture all subsequent

hospital admissions, enabling us to calculate future admission risk adjusted for key

confounding factors including preterm birth and congenital conditions.

However, several limitations should be noted. Our birth cohort excluded around 10%

infants born at home or in private hospitals. Most acute childhood infectious illness in the UK

is treated in NHS hospitals however our cohort excludes a small proportion of private

hospital admissions(27). We lack follow-up for children born in English hospitals who

migrated abroad before 5 years however this will be a small subset as only 0.02% of children

aged under 15 years leave the UK annually(28). Our cohort did not include out of hospital

deaths though UK total childhood deaths are low(29) so unlikely to have impacted results.

The known 356 in hospital deaths excluded were children who died in any subsequent

admission and represent a very small proportion of our cohort thus are unlikely to have

impacted on our findings. Also, childhood deaths in western Europe are commonly associated

with prematurity or co-morbidities from birth so therefore any confounding influence may

have already been accounted for by adjusting for these variables(30).

Our birth cohort is historical, however recent work suggests the characteristics of

children admitted to UK hospitals has not varied over time(31) so our results remain valid.

The impact of bronchiolitis on admissions over 5 years old is also not possible to estimate

from our study.

Observational studies using administrative data means some limitations relate to

biases from coding accuracy and completeness. However, HES’s median diagnostic accuracy

is estimated to be 80.3%(32) with completeness improving(18). Our case definition did not

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include laboratory diagnosed RSV infection, which would have improved diagnostic

accuracy. However, the National Institute for Health and Care Excellence (NICE)

recommends bronchiolitis is diagnosed clinically(6) so using only laboratory diagnosed cases

would have missed a large number. If hospitals do test for RSV, the results may not be

available for the discharge summary, from which HES coding is taken. Similarly, paediatric

respiratory admissions coded as asthma, wheeze or respiratory tract infections rely on

clinicians probabilistic diagnoses(26) so may be subject to misclassification bias but are

unlikely to affect our overall respiratory illness estimates. Bias will also arise from clinicians

being more likely to admit children with previous respiratory admissions as infants leading to

effect overestimation.

We restricted our bronchiolitis definition to infants who had a hospital admission up

to their first birthday, since our previous study found the median age of bronchiolitis

admission was around 4 months(7). However, we may have missed a small proportion of

infants with bronchiolitis over 1 year so could have underestimated subsequent respiratory

burden. A number of infants who were admitted for wheeze or asthma at their index

admission may in fact have had bronchiolitis. We did not include these in our case definition

and hence we may have underestimated the full extent of subsequent respiratory burden from

RSV and bronchiolitis. Using survival analysis, we censored follow-up once a child had their

first admission so our findings may underestimate risk as our previous study found 21% of

infants admitted with bronchiolitis had more than one admission(7).

Finally, we adjusted for several known confounders such as sex, being preterm and

for children living in deprived households available in HES data however accuracy of

confounders was dependent on the completeness of HES clinical coding. The number of

children born prematurely or of low birth-weight in our cohort was 46,847(7.64%) and thus

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corresponds to published estimates of premature birth rates(33). It was not possible to

control for other known confounders such as breastfeeding and passive smoke exposure(34).

This is important to acknowledge given that smoke exposure may explain both the initial and

subsequent admissions and the evidence that after adjusting for smoke exposure the

association between bronchiolitis and deprivation reduces(35).

Population-attributable risk was calculated for the number of childhood respiratory

admissions up to age 5 years attributable to infant bronchiolitis admissions. However, given

the multiple causal factors associated with childhood respiratory health this calculation

provides only an estimation of the impact infant RSV has on subsequent healthcare resource

use.

Implications and Future Research

Our finding that an infant bronchiolitis admission is associated with a 3-to-5-fold

increased risk of subsequent childhood respiratory admission is important for health

professionals to communicate to parents. Clinicians should emphasise the importance of

reducing other respiratory health risk factors such as passive smoke exposure among this at-

risk group. The recently updated NICE guidelines on asthma(26) recommend doctors risk

stratify asthmatic children to improve care for those most at risk of adverse outcomes such as

hospital admissions. Our study emphasises that clinicians should consider the increased risk

an infant bronchiolitis admission represents when managing asthmatic children.

We recommend future studies should link laboratory virological data with large

population level admission data. Moore et al(2012), linked the Western Australian Data

Linkage System with routine respiratory pathogen testing in order to investigate the causative

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organism in respiratory admissions in children <5 years old(36) demonstrating this method’s

feasibility. Virological data studies would also increase understanding of the causative

organisms in paediatric respiratory admissions which is a complex area(4,37,38). Future

studies should attempt adjustment for environmental smoke exposure given its significance as

a risk factor(39). We also suggest the wider health burden from infant bronchiolitis on

disability, time taken off work to care for sick children and health service costs including

primary care(5) is considered.

Bronchiolitis admissions in England have been increasing in recent years(9,40)

though geographical variation(41) in admission rates suggests increases are driven by varying

admission thresholds as opposed to increasing disease incidence(8,9,40). Our study suggests

that there may be 2300 extra subsequent respiratory admissions in children under 5 years

attributable to infant bronchiolitis admissions(PAR 4.7%). Our findings are an important

consideration for future economic analyses of potential RSV prevention strategies. For

example, in a recently published gap analysis on RSV maternal immunisation a key question

identified was ‘To what extent do long-term sequelae influence the health impact and cost-

effectiveness of RSV maternal immunisation’(42). Our study suggests any future RSV

prevention strategy may reduce subsequent respiratory childhood morbidity among all

infants, not just those at high risk of RSV, particularly as 80% bronchiolitis cases affects

healthy term infants(7).

A recent study found infants who received RSV immunoprophylaxis had a 32%

decreased risk of bronchiolitis hospital admission(43). However, Palivizumab is unlikely to

be a solution for reducing the long-term burden from bronchiolitis in healthy infants given its

high costs. Interventional studies using Palivizumab, have shown that reductions in RSV-

disease are associated with reduced asthma and wheezing incidence in pre-term

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infants(44,45). This suggests future interventions may reduce both acute RSV disease and

subsequent respiratory outcomes. To our knowledge RSV vaccine models(46) have not

incorporated the associated longer term childhood respiratory admissions we have reported.

We suggest future RSV vaccine impact and cost effectiveness studies should consider the

impact on future respiratory childhood admissions.

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Conclusion

Hospital admission for bronchiolitis in infancy is associated with a 3-5-fold risk for

subsequent hospital admission with respiratory illness in children under 5 years. One in five

infants with bronchiolitis admission will have a subsequent admission for asthma, wheeze,

LRTI and URTIs in the first 5 years of life. This highlights substantial potential benefits from

vaccine development to reduce the childhood health burden caused by RSV.

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TablesTable 1: Baseline characteristics for infants admitted with bronchiolitis, RSV associated disease and those with no bronchiolitis admission. All figures shown as percentages.

Infants admitted with bronchiolitis,

n = 16,288

Infants admitted with RSV-associated disease,

n = 16,845

Infants with no admission for bronchiolitis,

n = 597,089

SexMale 59.0 59.0 51.1

Female 41.0 41.0 48.9Recorded comorbidity at birth 24.6 24.7 16.9

Premature birth 18.4 18.3 7.3IMD Group 1 9.8 9.9 12.1

2 14.5 14.5 12.1

3 19.6 19.7 174 29.4 29.4 21.05 26.7 26.5 27.4

Ethnicity White 70.5 70.2 76.8Other

Ethnicities 13.6 13.8 12.8

Not known or

stated 15.9 16.0 10.4

Ethnicity: White = White (British, Irish or other). Other Ethnicities = Mixed, Asian, Afro-Caribbean & Chinese. Not known or stated = Not known or stated.IMD group 1 = most deprived 0- 20%, 2 = 20-40%, 3 = 40-60%, 4 = 60 – 80%, 5 = least deprived 10%

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Table 2: Percentage of children with at least one respiratory admission, before 5 years of age, in those with previous infant bronchiolitis admissions and those without.

Infants admitted with bronchiolitis

No admission for bronchiolitis in infancy

Respiratory condition admission

21.7 (21.0-22.3) 7.62 (7.56 – 7.69)

Asthma admission 4.27 (3.96 – 4.58) 0.880 (0.856-0.903)

LRTI admission 6.77 (6.38-7.15) 2 (1.97-2.04)

URTI admission 11.9 (11.4 – 12.4) 4.75 (4.70 – 4.81)

Wheezing admission 4.84 (4.51 – 5.17) 0.884 (0.860-0.908)

95% confidence interval shown in brackets.

Table 3: Adjusted hazard ratios for respiratory admissions by subcategory comparing children with a previous admission for bronchiolitis in infancy to those without. Hazard ratios adjusted for sex, IMD, ethnicity, prematurity and comorbidity at birth.

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*baseline group boys.

Tables 4a-d: Population Attributable Risk Percent Calculation

Table 4a: Exposed and Non-exposed

Exposure Status Respiratory admission

No respiratory admission

Population

Exposed 3,538 12,750 16,288Not Exposed 45,352 551,381 596,733Column Totals 48,889 564,132 613,021

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Respiratory admission Hazard Ratio (adjusted) 95% CI

Bronchiolitis 2.82 2.72 – 2.92

Sex* 0.761 0.747 – 0.775

IMD 1.07 1.06 – 1.08

Prematurity 1.38 1.34 – 1.42

Comorbidity at birth 1.19 1.16 – 1.21

Asthma admission

Bronchiolitis 4.35 4.00 – 4.73

Sex 0.569 0.538 – 0.601

IMD 1.14 1.11 – 1.16

Prematurity 1.40 1.28 – 1.52

Comorbidity at birth 1.11 1.04 – 1.19

LRTI admission

Bronchiolitis 3.10 2.91 – 3.31

Sex 0.929 0.897 – 0.962

IMD 1.03 1.02 – 1.05

Prematurity 1.65 1.57 – 1.75

Comorbidity at birth 1.28 1.23 – 1.34

URTI admission

Bronchiolitis 2.34 2.23 - 2.45

Sex 0.768 0.750 – 0.786

IMD 1.09 1.08 – 1.10

Prematurity 1.29 1.24 – 1.35

Comorbidity at birth 1.20 1.17 – 1.24

Wheezing admission

Bronchiolitis 5.02 4.64 – 5.44

Sex 0.573 0.543 – 0.605

IMD 1.00 0.983 – 1.02

Prematurity 1.50 1.38 – 1.63

Comorbidity at birth 1.16 1.09 – 1.24

Table 4b: Rate of Respiratory Admissions

RateExposed 0.2172Unexposed 0.076Whole population (birth cohort) 0.079751691

Table 4c: Population Attributable Risk

Population Attributable Risk = Ip – Iu

Ip = 0.07975(Incidence of respiratory admissions in whole birth cohort population. Exposed and unexposed. With or without infant bronchiolitis admissions)

Iu = 0.07600(Incidence of respiratory admissions in those unexposed. Without infant bronchiolitis admission)

Population Attributable Risk = 0.07975-0.07600 = 0.00375

Table 4d: Population Attributable Risk Percent

Population Attributable Risk percent = I p - I u x 100Ip

Population Attributable Risk percent = 0.07975 - 0.07600 x 1000.07975

Population Attributable Risk percent (PAR%) = 0.0470

Respiratory hospital admissions between aged 1-5 years attributable to infant bronchiolitis within our birth cohort

= PAR (0.0470) * Total Respiratory Admissions in birth cohort (48,889) = 2297 admissions

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Appendix 1:

Figure 1:

Kaplan-Meier Survival Estimates showing the relationship between admissions for RSV associated disease or bronchiolitis in infancy and subsequent admissions for respiratory disease between 1-5 years. Blue line – infants with no admission for bronchiolitis. Red line – infants with admission for bronchiolitis.

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a. RSV-associated disease and respiratory admissions b. Bronchiolitis and respiratory admissions

d. Bronchiolitis and wheezing admissionsc. Bronchiolitis and asthma admissions

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e. Bronchiolitis and LRTI admissions f. Bronchiolitis and URTI admissions

Appendix 2:

ICD10 Codes Exposure, bronchiolitis admissions (primary diagnosis field):

J21.0, J21.1, J21.8 and J21.9

ICD10 Codes for Exposure, RSV-associated admissions for sensitivity analysis:

J205, J210, J121, J209, J219, J128, J129, J180, J189 and J22.

ICD10 Codes for Outcomes, admissions for acute respiratory illness:

Asthma: o J45.0, J45.1, J45.8, J45.9,o J46.

Wheezing: o R06.2.

LRTI: o J12.0, J12.1, J12.2, J12.3, J12.8, J12.9, o J13, o J14, o J15.0-J15.9, o J16.0 & J16.8, o J17.1, J17.2, J17.3, J17.8, o J18.0, J18.1, J18.2, J18.8, J18.9,o J20.0-J20.9,o J22.

URTI: o J00, o J01.0-4, J01.8-9,o J02.0, J02.8-9,o J03.0, J03.8-9,o J04.0-2,o J05.0-1,o J06.0, J06.8-9,o J09,o J10.0, J10.1 J10.8 o J11.0, J11.1, J11.8.

ICD10 Codes for Prematurity or low birth weight:

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P05, P05.0-2, P05.9 P07, P07.0-3

ICD10 Codes for Comorbidities:

Immunodeficiency: D80, D81, D82, D83, D84 and D89 which includes diagnoses such as hypogammaglobulinemia and severe combined immunodeficiency.

Cystic fibrosis: E84.

Chronic lung disease: P27 – Chronic respiratory disease originating in the perinatal period and P28 – Other chronic respiratory diseases originating in the perinatal period.

Congenital heart diseases: Q20, Q21, Q22, Q23, Q24, Q25, Q26, Q27, Q28.)

Nervous system congenital anomalies: Q00 to Q07 which incorporates conditions such as spina bifida, anencephaly and other congenital malformations of the nervous system.

Other congenital anomalies & perinatal conditions: A broad range of congenital anomalies and perinatal conditions with ICD-10 P- and Q- codes, excluding those included within other definitions listed above, such as codes for chronic lung disease.)

Down’s syndrome: Q90.

Cerebral palsy: G80.

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