Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life.

Abstract

An increased prevalence of asthma/recurrent wheeze (RW), clinical allergy and allergic sensitisation up to age 13 years has previously been reported in subjects hospitalised with respiratory syncytial virus (RSV) bronchiolitis in their first year of life compared with matched controls. A study was undertaken to examine whether these features persist into early adulthood, to report longitudinal wheeze and allergy patterns, and to see how large and small airway function relates to RSV infection and asthma.
Follow-up at age 18 years was performed in 46 of 47 subjects with RSV and 92 of 93 controls. Assessments included questionnaire, clinical examination, skin prick tests, serum IgE antibodies to inhaled allergens, blood eosinophils, fraction of exhaled nitric oxide (FeNO), spirometry, multiple breath washout (lung clearance index, LCI) and dry air hyperventilation challenge.
Increased prevalence of asthma/RW (39% vs 9%), clinical allergy (43% vs 17%) and sensitisation to perennial allergens (41% vs 14%) were present at age 18 in the RSV cohort compared with controls. Persistent/relapsing wheeze associated with early allergic sensitisation predominated in the RSV cohort compared with controls (30% vs 1%). Spirometric function was reduced in subjects with RSV with or without current asthma, but not in asthmatic controls. LCI was linked only to current asthma, airway hyperresponsiveness and FeNO.
Severe early RSV bronchiolitis is associated with an increased prevalence of allergic asthma persisting into early adulthood. Small airway dysfunction (LCI) is related to current asthma and airway inflammation but not to RSV bronchiolitis. Reduced spirometry after RSV may reflect airway remodelling.

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doi: 10.1136/thx.2009.121582
published online June 27, 2010Thorax

Nele Sigurs, Fatma Aljassim, Bengt Kjellman, et al.
of life
after severe RSV bronchiolitis in the first year
Asthma and allergy patterns over 18?years

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Asthma and allergy patterns over 18 years after
severe RSV bronchiolitis in the first year of life
Nele Sigurs,1Fatma Aljassim,2,3Bengt Kjellman,4Paul D Robinson,5,6
Fridrik Sigurbergsson,7Ragnar Bjarnason,8Per M Gustafsson2,4,9
ABSTRACT
Background An increased prevalence of asthma/
recurrent wheeze (RW), clinical allergy and allergic
sensitisation up to age 13 years has previously been
reported in subjects hospitalised with respiratory
syncytial virus (RSV) bronchiolitis in their first year of life
compared with matched controls. A study was
undertaken to examine whether these features persist
into early adulthood, to report longitudinal wheeze and
allergy patterns, and to see how large and small airway
function relates to RSV infection and asthma.
Methods Follow-up at age 18 years was performed in
46 of 47 subjects with RSV and 92 of 93 controls.
Assessments included questionnaire, clinical
examination, skin prick tests, serum IgE antibodies to
inhaled allergens, blood eosinophils, fraction of exhaled
nitric oxide (FeNO), spirometry, multiple breath washout
(lung clearance index, LCI) and dry air hyperventilation
challenge.
Results Increased prevalence of asthma/RW (39% vs
9%), clinical allergy (43% vs 17%) and sensitisation to
perennial allergens (41% vs 14%) were present at age
18 in the RSV cohort compared with controls. Persistent/
relapsing wheeze associated with early allergic
sensitisation predominated in the RSV cohort compared
with controls (30% vs 1%). Spirometric function was
reduced in subjects with RSV with or without current
asthma, but not in asthmatic controls. LCI was linked
only to current asthma, airway hyperresponsiveness and
FeNO.
Conclusions Severe early RSV bronchiolitis is
associated with an increased prevalence of allergic
asthma persisting into early adulthood. Small airway
dysfunction (LCI) is related to current asthma and airway
inflammation but not to RSV bronchiolitis. Reduced
spirometry after RSV may reflect airway remodelling.
INTRODUCTION
Respiratory syncytial virus (RSV) infection is the
most common cause of severe bronchiolitis in
infants.1It is now established that early severe viral
lowerrespiratorytract
frequently followed by recurrent wheeze, asthma
and allergy during childhood.2 3
A number of previous studies have investigated
the association between RSV infection in infancy
and later development of asthma, although differ-
ences in timing and severity of RSV infection exist
between studies. The Tucson Children’s Respira-
tory Study (a birth cohort study) reported an
increased prevalence of respiratory symptoms until
age 11 and residual impaired lung function at age 13
in those experiencing a relatively mild RSV LRTI
infections (LRTI)are
(not requiring hospitalisation) during the first
3 years of life.4Impaired lung function at age 10 has
also been reported following hospitalisation in the
first year with proven LTRI.5Recently, data from
a cohort previously hospitalised in the first 2 years
of life and followed up at 18e20 years suggested
that this impairment may persist into early adult-
hood.6Histopathology studies of fatal RSV bron-
chiolitis demonstrate extensive damage to the
airway epithelium and marked small airway
obstruction,7yet the presence of persistent small
airway damage in later life is unclear. In adult
asthma, small airway dysfunction is closely asso-
ciated with bronchial hyper-responsiveness,8
a fundamental component of asthma correlated to
disease severity.10
Our cohort represents infants aged <1 year with
severeprimary RSVbronchiolitis
months of age at hospitalisation). We have previ-
ously demonstrated increased prevalence of asthma
or recurrent wheeze (RW) and allergic sensitisation
compared with a matched control cohort at ages 3,
7 and 13 years.11e13In this paper we present the
18-year follow-up data together with a longitudinal
analysis of wheeze and allergy patterns. The
primary aim was to see if the higher prevalence of
asthma or RW, clinical allergy and allergic sensiti-
sation persist at age 18. The secondary aims were to
describe the wheeze patterns in both cohorts and to
investigate how large and small airway function
relate to severe RSV bronchiolitis, current asthma,
airway hyper-responsiveness (AHR) and markers of
allergic inflammation.
9
(43/47
#6
METHODS
The study design is summarised in table 1. Forty-
seven children aged <1 year hospitalised with RSV
LRTI14between December 1989 and April 1990
constituted the index group. An age- and gender-
matched control group (n¼93) was recruited from
children attending the same child healthcare
centres as the index cases. Both cohorts were
followed up prospectively at ages 1, 3, 7, 13 and
18 years. Diagnosis of bronchiolitis was originally
based on criteria published by Court,15but was also
consistent with other later published criteria.16
Demographic details at age 18 are given in table 2.
Structured questionnaires were completed at all
follow-up time points to record demographic,
hereditary and clinical symptoms of allergy or
wheeze. A clinical examination was also performed.
The investigations performed at each assessment
are summarised in table 1. Details on skin prick
tests (SPT) and serum IgE tests are given in our
<Supplementary tables are
published online only. To view
these files please visit the
journal online (http://thorax.bmj.
com).
1Department of Paediatrics,
Bora ˚s Central Hospital, Bora ˚s,
Sweden
2Queen Silvia Children’s
Hospital, Go ¨teborg, Sweden
3Department of Paediatrics,
Alwasl Hospital, Dubai Health
Authority, Government of Dubai,
UAE
4Department of Paediatrics,
Central Hospital, Sko ¨vde,
Sweden
5Department of Respiratory
Medicine, The Children’s
Hospital at Westmead, Australia
6The Children’s Hospital at
Westmead Clinical School,
Discipline of Paediatrics and
Child Health, Faculty of
Medicine, University of Sydney,
Australia
7Emergency Department,
Landspitali University Hospital,
Reykjavik, Iceland
8University of Iceland,
Department of Paediatrics,
Landspitali University Hospital
Iceland, Reykjavik, Iceland
9The Sahlgrenska Academy at
the University of Gothenburg,
Gothenburg, Sweden
Correspondence to
Dr Nele Sigurs, Department of
Paediatrics, Bora ˚s Central
Hospital, Bora ˚s S-50182,
Sweden;
nele.sigurs@vgregion.se
Received 14 June 2009
Accepted 2 April 2010
Sigurs N, Aljassim F, Kjellman B, et al. Thorax (2010). doi:10.1136/thx.2009.121582
Copyright Article author (or their employer) 2010. Produced by BMJ Publishing Group Ltd (& BTS) under licence.
1 of 8
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previous publications.11e13The specific IgE assay method used
(ImmunoCAP) was consistent throughout the study period.
Spirometry was performed at baseline from age 7 and post-
bronchodilator at ages 13 and 18 years, according to American
Thoracic Society recommendations,17and expressed as standard
deviation scores (z-scores) using recently published normative
data.18 19Inhaled long-acting b2agonists were withheld for 24 h
and short-acting b2agonists or cromoglycates for 6 h prior to
testing. Inhaled corticosteroids (ICS), if used, were not discon-
tinued. Isocapnic dry air hyperventilation challenge (DACh) was
performed after baseline spirometry at age 13 and 18 years
(described in more detail in the online supplement). At age 18,
prior to these lung function tests, the fraction of nitric oxide in
expired air (FeNO) was measured in duplicate at an expiratory
flow of 50 ml/s using the Niox Mino (Aerocrine, Stockholm,
Sweden) and the mean FeNO result reported.
Multiple-breath washout (MBW) was performed before
spirometry using sulfur hexafluoride (SF6) as the marker gas and
a mass spectrometer for gas analysis and as previously described
in detail elsewhere.20Lung clearance index (LCI) was calculated
as the number of lung volume turnovers (ie, the cumulative
expired volume divided by the functional residual capacity)
needed to lower the end-tidal tracer gas concentration to 1/40th
of the starting concentration. A high value of LCI thus indicates
abnormal ventilation distribution. The mean LCI result from
three MBWs in each subject was reported. In a previous study
including healthy subjects, the mean, SD and upper limit of
Table 1
Study design and proportion of the 47 children in the RSV cohort and the 93 in the control cohort seen at follow-up during the study period
Age (years)
1 1.5, 2 and 2.5371318
Total number (RSV, controls)
% of cohort (RSV and controls)
Questionnaire
Examination
Skin prick tests (RSV, controls)
Egg white
Cat
Dog
Horse
Birch
Timothy
Mugworth
HDM (D pteronyssinus)
HDM (D farinae)
Mould (Cladosporium herbarum)
Mould (Alternaria alternata)
Blood samples
IgE to food allergens (Fx5)
IgE to inhaled allergens (Phadiatop)
Blood eosinophil counts
Lung function tests
Spirometry
Multiple breath washout (LCI)
FeNO
DACh
47, 93
100
3
3
3 (47, 92)
3
47, 93
100
3
47, 93
100
3
3
3 (45, 92)
3
3
47, 93
100
3
3 (46, 89)
3 (44, 89)
3
3
3
3
3
3
46, 92
98.5
3
3 (45, 89)
3 (42, 87)
46, 92
98.5
3
3 (42, 87)
3 (41, 85)
3
3
3
3
3
3
3
3
3
3
3 (44, 86)
3
3
3
3
3
3
3
3
3
3
3 (41, 85)
3
33
3
3
3
3
3 (44, 87)
3
333 (41, 85)
3 (40, 86)
3 (42, 86)
3
3 (41, 86)
3 (42, 86)
3 (41, 86)
3 (44, 86)
3
3 (44, 86)
3
3 (43, 86)
Numbers in parentheses (RSV, controls) if differed from numbers followed up at that time point.
A skin prick test weal with a mean diameter $3 mm was regarded positive. Phadiatop (Pharmacia Upjohn Diagnostics AB, Uppsala, Sweden) is a screening test for antibodies to inhaled
allergens. Fx5 (Pharmacia Upjohn Diagnostics AB, Uppsala, Sweden) is a screening test for food allergens.
HDM, house dust mite; DACh, dry air hyperventilation challenge; LCI, lung clearance index; FeNO, fractional exhaled nitric oxide; RSV, respiratory syncytial virus.
Table 2
syncytial virus (RSV) and control groups at age 18
Demographic data and family history of the respiratory
Variable RSV (n[46)Controls (n[92)
Weight (kg)
Height (cm)
Parental atopy
Parental asthma
Tobacco smoke exposure
Active
Passive (family member)
Indoor furred pets
65 (12)
174 (10)
30/46 (65%)
18/46 (39%)
70 (13)
174 (10)
52/92 (56%)
25/92 (27%)
10/45 (22%)
19/45 (42%)
24/46 (52%)
14/92 (15%)
40/92 (43%)
56/92 (61%)
Mean (SD) or proportions (percentages) of subjects are given. No significant differences
were seen between the groups.
Table 3
asthma/recurrent wheeze at four follow-up stations and the numbers of
cases in each wheeze pattern group for each cohort
Wheeze patterns defined from the presence/absence (+/?) of
Wheeze pattern
Age (years)
RSV (n[46) Controls (n[92)37 13 18
Never wheeze
Transient wheeze
Remitting/intermittent
?
+
?
?
?
+
+
?
?
+
+
?
+
+
?
?
?
+
+
+
+
?
?
+
?
+
+
?
?
?
+
?
+
?
+
+
?
+
+
+
?
?
?
?
?
?
?
?
?
+
+
+
+
+
+
+
14 (3, 11)***
7 (5, 2)
7 (4, 3)
69 (27, 42)
11 (8, 3)
4 (2, 2)
Late onset 4 (1, 3)7 (3, 4)
Persistent/relapsing14 (7, 7)*** 1 (1, 0)
Male, female distribution shown in parentheses.
Statistical evaluation refers to comparison of proportion of subjects in the different wheeze
pattern groups in the RSV and control cohorts: ***p<0.001.
RSV, respiratory syncytial virus.
2 of 8Sigurs N, Aljassim F, Kjellman B, et al. Thorax (2010). doi:10.1136/thx.2009.121582
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normality (ULN; mean + 1.96 SD) for LCI were 6.33, 0.43 and
7.17, respectively.20
At each follow-up time point, asthma was defined as $3
episodes of physician-verified wheeze and RW as $3 episodes of
parent-reported wheeze. Definitions of the wheezing patterns
over time are shown in table 3. Allergic rhinoconjunctivitis
(ARC) or clinical allergy was defined as rhinitis/conjunctivitis
occurring at least twice following exposure to a particular
allergen and unrelated to infection. Atopic dermatitis (AD) was
defined as a pruritic, chronic or chronically relapsing non-infec-
tious dermatitis. Allergic sensitisation implied occurrence of IgE
antibodies estimated by SPT and/or serum IgE tests. Current
disorder denotes symptoms over the last 12 months. Active and
passive smoke exposures, the presence of pets in the household,
and atopic or allergic heredity were assessed by questionnaire. A
positive history of atopic disease (AD, ARC or asthma) in first-
degree relatives (parents or siblings) was based on physician
diagnosis.
Statistical analyses
Yates’ corrected c2test was used for estimation of differences in
prevalence among groups and subgroups. One-way ANOVA was
used for parametric continuous variables and Tukey HSD for
subsequent group comparisons, if the overall F-test was signifi-
cant. A ManneWhitney test was used to test group differences
for non-parametric continuous variables. 95% CIs for mean and
median differences were calculated. c2tests for trend were used
to assess the combined influence of group allocation (RSV vs
control) and a parental history of physician-diagnosed asthma
on asthma/RW, ARC and sensitisation at age 18. Pearson
correlation tests were used to assess correlation of parametric
data, while the Spearman rank test was used for non-parametric
data. KaplaneMeier survival analysis was used to compare time
free from diagnosis of asthma, ARC, positive Phadiatop test or
positive SPT to any perennial allergen at a follow-up station; p
values based on Mantel-Cox log ranks were calculated. Multi-
variate logistic regression analyses were performed to establish
risk factors for asthma/RW, asthma alone and ARC at age 18.
ORs with 95% CI and p values were reported. Additionally,
conditional logistic regression tests were performed to adjust for
any degree of residual confounding due to the constitution of
the groups during the study period. SPSS Version 15.0 software
for Windows (SPSS Inc, Chicago, Illinois, USA), SPSS Sample-
Power 2.0 software and CI Analysis software version 2.1.2
(Trevor Bryant, University of Southampton) were used for the
statistical analyses.
RESULTS
Forty-six of the 47 subjects with RSV and 92 of the 93 controls
were followed up to 18 years of age. The demographic details of
the two cohorts at age 18 are summarised in table 2, and from
age 1e18 years in table E1 in the online supplement. No
significant differences were seen at age 18.
Cross-sectional data at age 18
Current asthma/RW was documented in 18 of 46 (39%) subjects
with RSVand 8 of 92 (9%) controls (p¼0.001). Current asthma
alone was found in 15 of 46 (33%) subjects with RSVand 6 of 92
(7%) controls (p<0.001). ARC was diagnosed in 20 of 46
subjects with RSV (43%) and 16 of 92 (17%) controls (p¼0.002).
No difference was found in the prevalence of AD (5 of 46 (11%)
subjects with RSV vs 8 of 92 (9%) controls).
The prevalence of sensitisation determined by SPT was
significantly increased in the RSV cohort compared with
controls to any animal dander (cat, dog, horse) (33% vs 11%;
p¼0.005) or any perennial (animal danders and house dust mites
(HDM)) (41% vs 14%; p¼0.001) (see table E2 in online
supplement).Ahigherprevalence
responses was seen in the RSV cohort (56% vs 28%, p¼0.005)
(see table E2 in online supplement). For the whole cohort, the
most commonly identified specific IgE antibodies performed in
those testing positive to Phadiatop screening were to ‘any
perennial’ (39 of 126, 31%), and were significantly increased in
subjects with RSV compared with controls (51% vs 21%;
p¼0.001).
Airway function data are summarised in table 4. Reduced
spirometric airway function (forced expiratory volume in 1 s
(FEV1), ratio of FEV1to forced vital capacity (FVC) and forced
expiratory flow at 25e75% FVC (FEF25e75)) was documented in
the RSV cohort compared with controls, but LCI did not differ.
AHR, bronchodilator response and blood eosinophil cell counts
were greater in the RSV cohort than in the controls, but FeNO
of positivePhadiatop
Table 4
Airway function and inflammatory markers in RSV and control groups at age 18 years
RSV (n[46)Control (n[92)95% CI for difference
Resting
FEV1(z-score)
FEV1/FVC (z-score)
FEF25e75(z-score)
LCI
Challenge (DACh)
Fall in FEV1(%)
Post-bronchodilation
Rise in FEV1(%)
FEV1(z-score)
FEV1/FVC (z-score)
FEF25e75(z-score)
Inflammatory markers
FeNO (ppb)
Blood eosinophil counts (3109/l)
?0.28 (0.93)
?0.68 (0.85)
?0.60 (0.77)
6.63 (0.52)
0.11 (1.08)
?0.08 (1.03)
?0.05 (0.85)
6.59 (0.43)
0.00 to 0.7 *
0.24 to 0.97 **
0.25 to 0.86 ***
?0.21 to 0.13
4.7 (0.0e37.8)3.1 (0.0e42.8)0.0 to 3.2*
5.9 (0.0e10.5)
0.16 (0.71)
?0.04 (0.88)
?0.01 (0.78)
3.1 (0.0e10.4)
0.38 (1.30)
0.42 (0.95)
0.38 (0.83)
0.5 to 3.4**
-0.18 to 0.61
0.11 to 0.80 **
0.09 to 0.69 *
14 (6e84)
0.20 (0.04e0.57)
13 (5e74)
0.14 (0.01e0.79)
?1 to 5
0.01 to 0.10 **
Data are shown as mean (SD) or median (range).
For normally distributed data, differences between the two groups are shown with 95% CI for the mean values and for non-normally distributed data as the 95% CI for the medians.
*p<0.05, **p<0.01, ***p<0.001.
For exact number of subjects in RSV and control group performing each test, see Table 1.
DACh, isocapnic dry air hyperventilation challenge; FEF25e75, forced expiratory fraction at 25e75% forced vital capacity; FeNO, fraction exhaled nitric oxide; FEV1, forced expiratory volume in
1 s; FVC, forced vital capacity; LCI, lung clearance index; ppb, parts per billion; RSV, respiratory syncytial virus.
Sigurs N, Aljassim F, Kjellman B, et al. Thorax (2010). doi:10.1136/thx.2009.121582 3 of 8
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was not. FEV1/FVC and FEF25-75remained lower in the RSV
cohort after bronchodilation. Subjects with RSV had lower
spirometry results than the controls, irrespective of current
asthma/RW diagnosis (table 5). Spirometry findings were similar
in controls with or without current asthma/RW. LCI was
significantly raised in subjects with RSV (p¼0.006) and controls
(p¼0.033) with current asthma/RW compared with corre-
sponding subjects without asthma (see table E3 in online
supplement). Only LCI differed significantly between the
controls with and those without current asthma/RW (see table
E4 in online supplement). In the RSV cohort, the maximum
percentage fall in FEV1after dry air challenge correlated signifi-
cantly with LCI (r2¼0.44; p<0.001), FeNO levels (r2¼0.26;
p<0.001) and with blood eosinophil counts (r2¼0.12; p¼0.011),
Table 5
Airway function and inflammatory markers in RSV versus control subjects with or without current asthma/RW at age 18 years
Current asthma/RW No current asthma/RW
RSV (n[18)Controls (n[8)95% CI for difference RSV (n[24)Controls (n[78) 95% CI for difference
Resting
FEV1(z-score)
FEV1/FVC (z-score)
FEF25e75(z-score)
LCI
Challenge (DACh)
Fall in FEV1(%)
Post-bronchodilation
Rise in FEV1(%)
FEV1(z-score)
FEV1/FVC (z-score)
FEF25e75(z-score)
Inflammatory markers
FeNO (ppb)
Blood eosinophils (3109/l)
?0.64 (0.85)
?0.89 (0.82)
?0.89 (0.71)
6.88 (0.63)
0.05 (0.77)
0.08 (1.37)
?0.06 (0.86)
6.89 (0.25)
?0.03 to 1.42
0.09 to 1.86*
0.17 to 1.50*
?0.46 to 0.49
0.00 (0.91)
?0.53 (0.86)
?0.38 (0.75)
6.44 (0.31)
0.11 (1.11)
?0.10 (1.00)
?0.05 (0.85)
6.56 (0.43)
0.00 to 0.77*
0.24 to 0.97**
0.25 to 0.86***
?0.21 to 1.29
8.5 (0.0e37.8)7.5 (0.3e42.8)
?5.5 to 11.5 3.6 (0.0e9.3)3.1 (0.0e22.1)
?0.9 to 1.8
6.5 (0.0e10.2)
?0.18 (0.79)
?0.23 (0.83)
?0.29 (0.76)
2.5 (0.0e9.9)
0.25 (1.05)
0.48 (1.06)
0.48 (0.72)
?0.3 to 6.3
?0.34 to 1.20
?0.09 to 1.50
0.11 to 1.43*
5.4 (0.0e10.5)
0.41 (0.81)
0.11 (0.90)
0.19 (0.74)
3.1 (0.0e10.4)
0.39 (1.15)
0.41 (0.95)
0.37 (0.84)
?0.0 to 3.2**
?0.18 to 0.61
0.11 to 0.80**
0.11 to 0.69*
22 (6e84)
0.33 (0.06e0.57)
15 (7e51)
0.16 (0.04e0.31)
?7 to 26
0.01 to 0.27*
13 (6e54)
0.16 (0.04e0.37)
12 (5e74)
0.14 (0.01e0.79)
?3 to 3
?0.02 to 0.06
Data are shown as mean (SD) or median (range).
For normally distributed data differences between the two groups are shown with 95% CI for the mean values and for non-normally distributed data as the 95% CI for the medians.
*p<0.05, **p<0.01, ***p<0.001.
DACh, isocapnic dry air hyperventilation challenge; FEF25e75, forced expiratory fraction at 25e75% forced vital capacity; FeNO, fraction exhaled nitric oxide; FEV1, forced expiratory volume in
1 s; FVC, forced vital capacity; LCI, lung clearance index; ppb, parts per billion; RSV, respiratory syncytial virus; RW, recurrent wheeze.
0
10
20
30
40
50
60
70
80
%
0
10
20
30
40
50
60
70
80
%
Any parent with asthma
RSV bronchiolitis
No
No
Yes
No
Yes
Yes
No
Yes
Any parent with asthma
RSV bronchiolitis
No
No
Yes
No
Yes
Yes
No
Yes
Any parent with asthma
RSV bronchiolitis
No
No
Yes
No
Yes
Yes
No
Yes
Any parent with asthma
RSV bronchiolitis
No
No
Yes
No
Yes
Yes
No
Yes
6 2 / 3
66 / 5
82 / 8
8 1 / 01
100 . 0<p
62 / 6
66 / 01
82 / 01
8 1 / 01
100 . 0<p
0
10
20
30
40
50
60
70
80
90
100
4 2 / 7
16 / 91
42 / 01
7 1 / 31
30 0 . 0=p
%
10 0 . 0<p
0
10
20
30
40
50
60
70
80
90
42 / 6
95 / 6
42 / 8
61 / 9
%
AB
CD
Figure 1
current positive skin prick test to perennial allergens in respiratory syncytial virus (RSV) and control cohorts with respect to heredity for asthma. c2
test for trend was used in all graphs and error bars denote 95% CI.
Proportion (%) with (A) current asthma/recurrent wheeze, (B) current allergic rhinoconjunctivitis, (C) current positive Phadiatop test and (D)
4 of 8Sigurs N, Aljassim F, Kjellman B, et al. Thorax (2010). doi:10.1136/thx.2009.121582
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but not with spirometry results (see table E5 in online supple-
ment). Among the subjects with current asthma/RW, regression
analyses also demonstrated significant relationships between
LCI and the maximum percentage fall in FEV1 after dry air
challenge (r2¼0.26; p¼0.005) and between LCI and FeNO
(r2¼0.29; p¼0.003).
Family history and other risk factors for asthma and ARC
at age 18
A family history of asthma and atopy did not differ between the
RSV and control cohorts at age 18. A number of risk factors for
current asthma/RW, current asthma and current ARC, respec-
tively, were assessed using multivariate logistic regression anal-
yses including both cohorts. For current asthma/RW and for
current asthma, the risk factors included were: allocation (RSV/
control), gender, domestic furred pets in the first year of life,
parental smoking in the first year of life, own smoking at age 18,
current ARC of the subjects themselves, physician-diagnosed
parental ARC and physician-diagnosed parental asthma.
For current asthma/RW, only RSV (OR 6.2; 95% CI 2.0 to
19.2; p<0.001) and current ARC of the subjects (OR 6.1; 95% CI
2.1 to 18.1; p<0.001) were significant independent risk factors.
For current asthma alone, similar results were found (RSV: OR
7.2 (95% CI 2.1 to 23.9; p<0.001); current ARC: OR 4.4 (95% CI
1.4 to 14.0; p<0.001)).
The risk factors included in the analysis for current ARC were
the same, except for current ARC of the subjects. Only RSV
(OR 3.6; 95% CI 1.6 to 8.5; p¼0.003) was a significant inde-
pendent risk factor. Corresponding conditional logistic regres-
sion tests gave similar results (see table E6 in the online
supplement).
Numerically, the RSV subgroup with a parental history of
asthma had a higher prevalence of asthma/RW, ARC and positive
sensitisation than the RSV subgroup without parental asthma,
but no significant differences were found (p¼0.058e0.308).
The statistical power to detect significant differences between
the RSV subgroups was <50%. For the two cohorts analysed
together, however, the combination of RSV allocation and
history of parental asthma resulted in significant trends for
disease and sensitisation (figure 1AeD).
Longitudinal data over the entire study period: subjects with RSV
versus controls
KaplaneMeier survival plots for time free from asthma diag-
nosis, ARC diagnosis, positive Phadiatop test or positive SPTare
shown in figure 2AeD. The RSV group had significantly shorter
time free from these diagnoses and test findings.
Reduced lung function in the RSV cohort was evident from
the age of 7 years (mean (SD) baseline FEF25e75z-scores in RSV
0
20
40
60
80
100
181373
Age at follow-up visit (years)
18 1373
Age at follow-up visit (years)
181373
Age at follow-up visit (years)
18
1373
Age at follow-up visit (years)
RSV
Controls
%
0
20
40
60
80
100
%
0
20
40
60
80
100
%
0
20
40
60
80
100
%
A
B
CD
Figure 2
3, 7, 13 and 18 years (log rank (Mantel-Cox) c221.0; df 1; p<0.001); (B) an allergic rhinoconjunctivitis diagnosis at follow-up at ages 3, 7, 13 and
18 years (log rank (Mantel-Cox) c215.5; df 1; p<0.001); (C) a positive Phadiatop test at follow-up at ages 3, 7, 13 and 18 years (log rank (Mantel-Cox)
c28.3; df 1; p¼0.004); and (D) a positive skin prick test at follow-up at ages 3, 7, 13 and 18 years (log rank (Mantel-Cox) c28.0; df 1; p¼0.005).
Proportion (%) of subjects in the respiratory syncytial virus and control cohorts who never had (A) an asthma diagnosis at follow-up at ages
Sigurs N, Aljassim F, Kjellman B, et al. Thorax (2010). doi:10.1136/thx.2009.121582 5 of 8
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group vs controls at age 7: ?0.63 (1.04) vs ?0.22 (0.95) (95% CI
0.05 to 0.77; p¼0.025); at age 13: ?0.58 (0.77) vs ?0.12 (0.78)
(95% CI 0.17 to 0.74; p¼0.002). At ages 13 and 18 a greater fall
in FEV1after DACh was seen in subjects with RSV.13
Wheeze patterns up to age 18 years
The persistent/relapsing asthma/RW pattern occurred more
frequently in the RSV cohort with fewer non-wheezers in the
RSV group (table 3). No difference in other wheeze patterns was
seen. All 14 individuals with a persistent/relapsing asthma/RW
pattern in the RSV cohort had current symptoms on at least
two time points (seven on all four and six on three occasions).
Asthma/RW was noted from age 3 in 11 of 14 subjects in this
group. The one individual in the control group with persistent/
relapsing asthma had symptoms at all occasions from age 7.
Nine subjects with RSV (7 with persistent/relapsing asthma/
RW and 2 with late onset asthma/RW) and 3 control subjects
with late-onset asthma/RW were treated with ICS (p¼0.002).
The persistent/relapsing group (14 RSV and 1 control) was
characterised by the highest prevalence of co-existing ARC
(figure 3A) and sensitisation (figure 3B). The significantly higher
prevalence of sensitisation was evident at ages 3, 7 and 13, and
similarly for ARC at age 7 and 13 (data not shown).
At 18 years of age the persistent/relapsing wheeze group had
significantly lower airway function (FEV1, FEV1/FVC and
FEF25e75z-scores), higher LCI and AHR than the non-wheeze
group (table 6). Bronchodilator response, FeNO and blood eosin-
ophil counts were significantly increased compared with never
wheezers only in the persistent/relapsing asthma/RW group.
DISCUSSION
The previously reported over-representation of asthma (and
asthma/RW), clinical allergy and allergic sensitisation in this
RSV cohort persisted into early adulthood. The high prevalence
of current asthma/RW in the RSV cohort was due to a high
proportion of subjects with early-onset allergy-associated
wheezing persisting through childhood and adolescence, and
was accompanied by reduced airway function, elevated FeNO
and eosinophil counts. A history of hospitalisation for RSV
bronchiolitis was the only significant risk factor identified at age
18 for current asthma/RW, asthma alone or ARC.
At age 18, spirometry results were reduced in subjects with
RSV with or without current asthma/RW compared with
corresponding controls, but subjects with RSV without current
asthma did not show evidence of small airway dysfunction as
measured by LCI. Spirometry results showed no relationship
with AHR or markers of allergic inflammation. In contrast,
small airway dysfunction (LCI) correlated with current asthma,
AHR and FeNO, a marker of ongoing allergic airway inflam-
mation.
This controlled follow-up study and its findings are unique. It
describes the development of asthma and allergy prospectively
after severe primary RSV bronchiolitis in the first year life, and
has involved several follow-up time points from infancy to
young adulthood, all with very high attendance rates. The
subsequent high frequency of early-onset allergic asthma
persisting to age 18 has not previously been reported. Only two
other prospective studies of RSV have documented a high
prevalence of early sensitisation comparable to ours at 1 year21
and 3 years of age.22
The debate between a causal or genetic predisposition rela-
tionship between RSV and asthma has continued for decades
and cannot be answered by this study. Two recent large registry-
based studies have attempted to answer this question, with each
declaring opposite conclusions.23 24The weaknesses in the study
designs and the difficulties in answering this question have been
highlighted in a recent editorial.25RSV-positive infants with
wheezing may include both those with primary RSV LRTI or
those with an existing non-atopic or atopic wheezing disorder
exacerbated by RSV. In our cohort, 91% of the index subjects
were 6 months or younger when admitted and only one had
a previous history of lower airway symptoms, which strongly
suggests that our cohort comprises subjects with early primary
severe RSV LRTI. It is thought that early infancy, with a rela-
tively Th-2 skewed immune system, may constitute a particu-
larly vulnerable period of life for subsequent development of
asthma following severe viral LRTI.3Viral airway infections and
atopy may interact in a multiplicative way to promote asthma
development in young childhood.26In addition, predisposition
to both early severe RSV bronchiolitis and allergic sensitisation
may be related to the interleukin (IL)-13/IL-4 gene locus.27
Potential hereditary susceptibility to RSV bronchiolitis has also
been reported.28
Potentialconfoundingfactorsdoexistwithinourcohort.Mallia
and Johnston29have previously suggested that the higher rate of
asthmainourRSVcohortcomparedwithcontrolscouldbedueto
selection bias generated by the selection of controls contempora-
neously from the same child healthcare centres as the indexcases.
Theoretically, our selection process during an ongoing RSV
epidemic could generate controls with a lower susceptibility for
severe RSV bronchiolitis and a lower risk for subsequent allergic
asthmaifsevereRSVbronchiolitisandsubsequentallergicasthma
are markers of the same genotype. There are two main reasons
0
10
20
30
40
50
60
70
80
Remitting/
intermittent
11
Transient No wheezePersistent/
relapsing
15
14
Late onset
%
* * *
* *
111883
14
69
No, total
No, RSV
No, controls
4
7
7
4
7
1 11
14
13
1
9
4
5
9
5
4
17
7
10
77
12
65
Wheeze phenoype
0
Remitting/
intermittent
Transient No wheezePersistent/
relapsing
Late onset
No, total
No, RSV
No, controls
Wheeze phenoype
10
20
30
40
50
60
70
80
90
100
* * *
%
A
B
Figure 3
in different wheezing phenotypes (overall c2p<0.001, **p<0.01,
***p<0.001 vs the no-wheeze phenotype) and (B) positive Phadiatop
test in different wheezing phenotypes (overall c2p<0.001, ***p<0.001
vs the no-wheeze phenotype). Error bars denote 95% CI. RSV, respiratory
syncytial virus.
Proportion (%) of subjects with (A) allergic rhinoconjunctivitis
6 of 8Sigurs N, Aljassim F, Kjellman B, et al. Thorax (2010). doi:10.1136/thx.2009.121582
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why we do not feel that selection bias significantly affected our
results. First, the RSV cohort had the same ARC and asthma
parental/sibling heredity prevalence as the controls, and the RSV
and control cohorts had a similar prevalence of AD. Second, the
control group had a similar prevalence of current asthma/RW,
ARC and positive SPT at age 13 to a recent population-based
sample of 12e13-year-old Swedish children living in an over-
lappinggeographicalarea(8.5%,17%and22.5%,respectively).30 31
Ourstudywasintendedtobeadescriptivestudyand,assuch,was
not powered to detect differences in hereditary rates of allergic
disease/asthma between asthmatic and non-asthmatic index
cases. Fifty index cases in each group would have been required to
achieve adequate power. Nevertheless, there are indications
that early severe RSV bronchiolitis is associated with a greater
increased risk for subsequent asthma, clinical allergy and allergic
sensitisation when combined with a history of parental asthma
(figure 1 AeD).
The FEV1/FVC ratio and the FEF25e75, the most reliable and
the most sensitive spirometric indices of airway obstruction,
respectively, were reduced both at baseline and post-bronchodi-
lator in our RSV cohort. Airway obstruction was most
pronounced in subjects with a persistent/relapsing wheezing
pattern at age 18, and this pattern could be traced back to ages 7
and 13 years. Interestingly, spirometric indices were also reduced
in subjects with RSV without current asthma. These changes
may reflect premorbid airway function32or the presence of
airway remodelling due to a severe RSV infection occurring-
during a critical period of lung development, with or without
subsequent interaction with early allergic sensitisation.2
Young age at first wheezing episode is an important risk
factor for subsequent persistent asthma in sensitised cohorts.34
In the present study LCI was increased in both RSV and
control subjects with current asthma, while spirometry results
were impaired only in the subjects with RSV. Increased LCI can
result from non-uniformity of ventilation distribution among
lung regions sharing branch points in the conducting airway
zone or even more peripherally in the vicinity of the terminal
bronchioles.35 36These results suggest that residual small airway
dysfunction is not a result of RSV infection per se but is related
to a subsequent diagnosis of asthma. Peripheral airway
obstruction and the patchy distribution of airway disease are
both recognised characteristics of asthma.9 37Our findings are
consistent with other studies documenting raised LCI, despite
33
normal spirometry, in subjects with current mild asthma aged
5e15 years,38and normal small airway function in an RSV
cohort without asthma followed up at age 10 using single-
breath nitrogen washout.5The marked alveolarisation and
completion of distal airway formation occurring during the first
three years of life may compensate for the more peripheral
airway sequelae of early severe RSV infection, while more
proximal changes persist. Increased AHR was present in the
subjects with asthma, although not to the magnitude previ-
ously reported in other studies, in part due to the decision not to
withhold ICS prior to testing. A fall in FEV1of 10% or more
(mean 22.1%) was seen in 8 of 41 subjects with RSVand in 5 of
86 tested controls (mean 20.1%; p¼0.038; c2with Yates’
correction). Despite this, a significant correlation of LCI but not
spirometry with AHR was ween in our RSV cohort and
confirms the important findings of Downie et al.8LCI but not
spirometry was also significantly correlated with ongoing
airway inflammation (FeNO).
In summary, this study shows that severe primary RSV
bronchiolitis in the first year of life is frequently followed by
allergic asthma persisting into early adulthood. Subjects with
RSV with and without current asthma/RW have reduced airway
function as measured by spirometry. Ventilation inhomogeneity,
a measure of small airway function, is normal in subjects with
RSV without current asthma but is linked to current asthma,
AHR and ongoing airway inflammation. Our findings suggest
that early severe RSV bronchiolitis has lifelong consequences of
allergic asthma and airway remodelling.
Acknowledgements The authors thank Mrs Gunilla Holmgren Wallmyr for skilful
assistance at all follow-up visits in this study and Mr Salmir Nasic for statistical
advice.
Funding The study was supported by grants from the Regional Health Care Authority
of West Sweden, from Bora ˚s Hospital, the Fokus Foundation and SeBe’s Fund.
Competing interests None.
Ethics approval This study was conducted with the approval of the Human Research
Committee of the Medical Faculty at the University of Gothenburg. All parents and
subjects gave consent to the study.
Provenance and peer review Not commissioned; externally peer reviewed.
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Table 6
Airway function and inflammatory markers in the different wheeze pattern groups for the entire cohort at age 18 years
VariableNever wheezeTransient wheeze Remitting/intermittent wheeze Persistent/relapsing wheezeLate onset wheeze
Number of subjects
Airway function
FEV1(z-score)
FEV1/FVC (z-score)
FEF25-75(z-score)
LCI
FeNO (ppb)
Challenge (DACh)
Fall in FEV1(%)
Reversibility
Rise in FEV1(%)
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?0.62 (1.02)
?0.45 (0.85)
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?0.91 (0.88)*
?0.93 (0.73)**
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