Prednisolone reduces recurrent wheezing after
a first wheezing episode associated with
rhinovirus infection or eczema
Pasi Lehtinen, MD,aAino Ruohola, MD,aTimo Vanto, MD,aTytti Vuorinen, MD,b
Olli Ruuskanen, MD,aand Tuomas Jartti, MDaTurku, Finland
Background: Rhinovirus-induced early wheezing has been
Objective: We sought to investigate the risk factors for
recurrent wheezing and to determine post hoc the efficacy
of prednisolone in risk groups.
Methods: We followed for 1 year 118 children (median age, 1.1
years) who had had their first episode of wheezing and had
participated in a trial comparing prednisolone with placebo in
hospitalized children. Demographics and laboratory data were
obtained at study entry. The follow-up outcome was recurrent
wheezing (3 physician-confirmed episodes).
Results: Recurrent wheezing was diagnosed in 44 (37%) children.
Independent risk factors were age < 1 year, atopy, and maternal
asthma. The probability of recurrent wheezing was higher in
among placebo recipients (hazard ratio, 5.05; 95% CI, 1.00-25.41).
Prednisolone decreased the probability of recurrent wheezing in
children with eczema (0.15; 95% CI, 0.04-0.63) but not in those
without eczema (1.89; 95% CI, 0.83-4.29; P 5.007 for interaction).
Prednisolone was associated with less recurrent wheezing in the
95% CI, 0.83-5.00; P 5.017 for interaction).
Conclusion: Rhinovirus-induced early wheezing is a major
viral risk factor for recurrent wheezing. Prednisolone may
prevent recurrent wheezing in rhinovirus-affected first-time
wheezers. The presence of eczema may also influence the
response to prednisolone.
Clinical implications: A prospective trial is needed to test the
hypothesis that prednisolone reduces recurrent wheezing in
rhinovirus-affected wheezing children. (J Allergy Clin
Key words: Recurrent wheezing, rhinovirus, eczema, atopy, pred-
Acute wheezing affects one third of young children.1
Half of these children continue to wheeze, at least recur-
rently, until school age. The risk factors for recurrent
wheezing include host, environment, and genetic factors
such as male sex, eczema, atopy, rhinitis apart from colds,
older siblings, maternal smoking, maternal asthma, and
Hispanic ethnic background.1,2
Acute wheezing is predominantly related to viral res-
piratory infection.2-5Respiratory syncytial virus (RSV)
andbyschool-ageasthma in18%to37%of cases.6-12The
rates of recurrent wheezing associated with other respira-
tory viruses are not well known because viral diagnostic
tools have not been widely available. Rhinovirus is partic-
ularly interesting, because it is the second most common
virus, triggering early wheezing in as many as 45% of
cases.3-5Recently, rhinovirus-induced early wheezing
has been suggested as a new major risk factor, because it
has been followed by third-year wheezing in 65% of cases
and school-age asthma in 60% of cases.2,11
It would be of utmost importance to identify children
at high risk for recurrent wheezing and provide them
exacerbations,14many efficacy studies of early wheezing
have been discouraging. First episodes of RSV-induced
wheezing in infants do not respond to systemic corticoste-
roids at standard doses.15-18Furthermore, only 2 separate
reports have also analyzed nonviral factors.15,19In these
studies, atopy or systemic eosinophil priming has not
been associated with efficacy of systemic corticosteroids
in young children.
We recently showed that a short course of oral pred-
nisolone reduces recurrences over a 2-month period after
the first or second episode of wheezing associated with
HR: Hazard ratio
OR: Odds ratio
RSV: Respiratory syncytial virus
athe Department of Pediatrics, Turku University Hospital; and
Department of Virology, University of Turku.
Supported by the Academy of Finland, the Foundation for Pediatric Research,
the Finnish Cultural Foundation, the Paulo Foundation, and the Turku
University Foundation. Prednisolone and placebo were provided by
Leiras Pharmaceuticals Inc, Turku, Finland.
Disclosure of potential conflict of interest: The authors have declared that they
have no conflict of interest.
Received for publication July 19, 2006; revised November 6, 2006; accepted
for publication November 9, 2006.
Available online December 30, 2006.
Reprint requests: Tuomas Jartti, MD, Sirkkalankatu 4 C 59, FIN-20520 Turku,
Finland. E-mail: email@example.com.
? 2007 American Academy of Allergy, Asthma & Immunology
Asthma diagnosis and
rhinovirus infection or with above-average blood eosino-
had their first episode of wheezing. Our aim was to deter-
mine risk factors for recurrent wheezing and to assess
post hoc the long-term effects of prednisolone on the
As part of an efficacy trial of oral prednisolone on wheezing
requiring hospitalization, we conducted a prospective,1-year follow-
up of a cohort of children age 3 to 35 months who had experienced
their first episode of wheezing in their lives. The exclusion criteria
were inhaled or systemic corticosteroids within 4 weeks before the
the efficacy trial were randomized double-blindly to receive either
oral prednisolone (first dose 2 mg/kg, then 2 mg/kg/d in 3 divided
doses) or placebo.20No stratified randomization was done for partic-
ipants eligible for the follow-up cohort because the follow-up proto-
col was made and implemented during the conduct of the efficacy
trial. Written parental informed consent was obtained before com-
mencing the study, and the study protocol was approved by the
Ethics Committee of the Turku University Hospital.
Risk factor data
On initial admission, a nasopharyngeal mucus sample was
aspirated and a venous blood sample was obtained during the acute
(at study entry before randomization) and convalescent phases (2-3
weeks after discharge from the hospital). We used comprehensive
viral diagnostics including culture, antigen detection, PCR, and/or
serology to detect the following respiratory viruses: adenovirus,
coronaviruses (strains OC43 and 229), enteroviruses, human meta-
1, 2, and 3), rhinovirus, and RSV.21From the acute phase blood
sample, blood eosinophils and IgE antibodies for common allergens
(codfish, cow’s milk, egg, peanut, soybean, wheat, cat, dog, horse,
birch, mugwort, timothy, Cladosporium herbarum, and Dermato-
phagoides pteronyssinus; fluoroenzyme immunoassay, CAP FEIA,
Phadiatop Combi, Phadia, Uppsala, Sweden) were measured by the
Central Laboratory of Turku University Hospital. Age, sex, and pre-
maturity were recorded. The parents filled out a questionnaire on
other host and environment-related risk factors of recurrent wheez-
ing: physician-diagnosed eczema, parental history of allergy and/or
asthma, parental smoking, and day care.
The primary outcome was time to recurrent wheezing—that is,
time to the third physician-confirmed episode of wheezing within 12
months of the first episode at study entry. This was based on the
Finnish practice to start continuous inhaled corticosteroids in all
children at the time of the third episode of wheezing within 1 year.
The outcome was measured by clinical examination and parental
interview at a follow-up session 1 year after initial hospitalization.
All episodes of wheezing were confirmed by reviewing each child’s
Prematurity meant a gestational age less than 37 weeks. The
diagnosis of eczema had been made by the participants’ personal
physicians according to typical symptoms that included pruritus,
typical morphology and distribution of eczematous lesions, and
chronicity of disease.22Atopy referred to positive IgE antibodies
against at least 1 of the listed allergens (Phadiatop Combi; detection
viral subgroups according to the viral etiology of the first episode of
wheezing at study entry: rhinovirus group (rhinovirus diagnosed
rhinovirus negative group (any other viruses except RSV or rhinovi-
rus diagnosed or no viruses found). This groupingwas based on the a
priori hypothesis that rhinovirus-associated wheezing is a stronger
risk factor for recurrences than RSV-associated wheezing,2,11and it
agrees with the viral grouping of Lemanske et al.2
We analyzed the host and environment-related risk factors by
Kruskal-Wallis ANOVA followed by the Mann-Whitney U test, and
by the x2test, as appropriate. We did not calculate statistical signifi-
cances for the proportions of outcomes in the risk factor groups be-
cause we aimed to avoid multiple testing and because the primary
outcome included the time aspect. Instead, we used Cox proportional
hazards regression to identify any risk factors of prognostic signifi-
ity of recurrent wheezing. First, we analyzed in separate models the
interactions between treatment grouping and each risk factor. Then,
we used stepwise multivariable model to identify independent risk
interaction terms were included that showeda potential effect on out-
come. We used a backward stepwise procedure in which we elimi-
nated factors or interaction terms one by one according to the
highest P value >.05. The analyses were made using SPSS/PC 13.0
software (SPSS Inc, Chicago, Ill).
Of the 293 randomized patients, 131 children fulfilled
the criteria for the long-term follow-up (Fig 1). Lost to
follow-up were 13 children. Thus, the final study cohort
consisted of 118 children. Of them, 96 were clinically
examined and their parents personally interviewed, and
the parents of 22 children were interviewed by phone.
Eleven children (9%) were treated for prolonged cough
with a continuous inhaled corticosteroid. They were cen-
sored from analyses at the time of the initiation of contin-
olone as the study drug. Their median age was 1.6 years,
and median blood eosinophil count was 0.3 3 109/L.
FIG 1. Study flow chart.
J ALLERGY CLIN IMMUNOL
VOLUME 119, NUMBER 3
Lehtinen et al 571
Asthma diagnosis and
whether it reappeared after discontinuing the inhaled cor-
ticosteroid. The median age of the final study cohort was
1.1 years (range, 0.3-2.9). Table I shows the distributions
of the host and environment-related risk factors. The risk
factor characteristics of prednisolone and placebo groups
were comparable (all P values > .28). However, the risk
factors were interrelated. Childrenwith eczema hadatopic
sensitization more often and RSV infection less often than
those without eczema (P 5 .017 and P 5 .014, respec-
ten had blood eosinophilia (?0.4 3 109/L; P 5 .006) and
rhinovirus infection (P 5 .001) than nonatopic children.
Within the 3 viral groups, the RSV group was younger
(P 5 .002) and less often had eczema (P 5 .014) and
eosinophilia (P < .001) than the 2 other viral groups
combined, and the rhinovirus group had atopy more
frequently than those without rhinovirus infection (P 5
Recurrent wheezing during the 1-year follow-up af-
fected 44 (37%) of the 118 children equally often in the
prednisolone group and the placebo group (Table I).
Recurrent wheezing was most often related to prematurity
(mean 33 gestational weeks) and atopy regardless of treat-
current wheezing. The proportions of children with recur-
rent wheezing seemed to be different among prednisolone
recipients and placebo recipients in relation to eczema,
maternal asthma, parental smoking, day care attendance,
and viral etiology, which indicated a possible interaction
between treatment and these risk factors. The separate
Cox regression models further suggested an interaction
between treatment grouping and eczema (P 5 .006), day
care attendance (P 5 .023), and the viral etiology of the
first episode of wheezing (P 5 .059). No interaction was
identified between treatment grouping and any other risk
factor (all P values > .3). The 3 suggestive interactions
were included in the multivariable model together with
recurrent wheezing were young age (<1 year), atopy, and
maternal asthma (Table II). Furthermore, a significant
interaction was detected between treatment grouping and
eczema status (P 5 .007) as well as between treatment
grouping and viral etiology (P 5 .017).
Subgroup analyses suggested that prednisolone, com-
pared with placebo, decreased the probability of recurrent
age,atopy, maternalasthma,andviral etiology,0.15;95%
CI,0.04-0.63) butnotin those without eczema (1.89; 95%
TABLE I. Distributions of risk factors and children with
recurrent wheeze in the entire cohort and in risk
Children with recurrent wheeze
(n 5 118)
44 (37%)22 (37%) 22 (38%)
<0.4 3 109/L
?0.4 3 109/L
53 (45%) 22 (42%)
65 (55%) 22 (34%)
78 (66%) 31 (40%)
40 (34%) 13 (33%)
20 (17%) 10 (50%)
98 (83%) 34 (35%)
35 (30%) 15 (43%)
82 (70%) 29 (35%)
24 (20%) 11 (46%)
93 (80%) 32 (34%)
84 (72%) 32 (38%)
32 (28%) 12 (38%)
103 (88%) 36 (35%)
8 (57%)5 (71%)
49 (41%) 20 (41%)
69 (59%) 24 (35%)
70 (59%) 28 (40%)
48 (41%) 16 (33%)
43 (36%) 10 (23%)
37 (31%) 14 (38%)
38 (32%) 20 (53%)
TABLE II. Significant risk factors and interaction terms
associated with recurrent wheeze according to the
Cox multivariable regression model
Risk factor or interaction termHR (95% CI)P value
Age <1 y
Treatment 3 eczema
Treatment 3 viral etiology
*P value for interaction between treatment grouping and eczema status.
?P value for interaction between treatment grouping and viral etiology.
J ALLERGY CLIN IMMUNOL
572 Lehtinen et al
Asthma diagnosis and
CI, 0.83-4.29). Moreover, in children whose first episode
of wheezing was induced by rhinovirus, prednisolone was
associated with less recurrent wheezing (HR adjusted for
young age, eczema, atopy, and maternal asthma, 0.19;
95% CI, 0.05-0.71). Treatment seemed to have no effect
on recurrences in the RSV group (2.12; 95% CI, 0.46-
9.76) or in the RSV/rhinovirus-negative group (2.03; 95%
CI, 0.83-5.00). Fig 2 illustrates the interactions showing
that prednisolone treatment provided no overall benefit,
but the treatment effect showed differences related to the
eczema and viral etiology of the first episode. Although
in the eczema and rhinovirus groups, the difference be-
tween prednisolone and placebo recipients is most ap-
parent during the first 3 months, the favorable effect of
prednisolone on children with eczema or rhinovirus infec-
tion persisted for the entire 1-year follow-up.
Our results indicate that rhinovirus-induced early
wheezing is a major viral risk factor for recurrent wheez-
ing. It seems to be a more important predictor than RSV-
induced disease. In our study, 50% of placebo recipients
infected by rhinovirus had recurrent wheezing within the
first year after the initial episode, compared with 17% of
RSV-positive and 46% of RSV/rhinovirus-negative chil-
dren. This is in agreement with 2 other recent studies that
have also used modern viral diagnostics.2,11In a previous
Finnish study on early wheezing in hospitalized children
(n 5 66), 60% had asthma at school age if rhinovirus-pos-
itive, whereas only 18% of RSV-positive cases and 29%
of rhinovirus-negative cases developed asthma (oddsratio
[OR], 4.1 for rhinovirus-positive compared with rhinovi-
rus-negative cases).11A study from the United States fol-
lowed a birth cohort with an increased risk of allergies or
asthma.2Of 275 infants, 65% with moderate-to-severe
wheezing associated with rhinovirus infection continued
to wheeze at the age of 3 years compared with 48% and
49% of infants infected by RSV or other viruses, respec-
tent wheezing was significantly higher in the rhinovirus
group (OR, 10) than in the RSV group (OR, 3.5) and in
the RSV/rhinovirus-negative group (OR, 4.6). These 3
studies from different centers show that rhinovirus infec-
tion–induced wheezing in young children is a major viral
risk factor for recurrent wheezing and/or development of
What is the plausible explanation for the increased
tendency of recurrences after rhinovirus-induced wheez-
ing? First, rhinovirus infections can invade the lower
airways, increase their inflammatory responses, and en-
hance airway hyperresponsiveness.23-27Second, as in the
other Finnish wheeze study, rhinovirus etiology and risk
factors for recurrences were interrelated in our popula-
tion.11This implies that these patient groups may be
connected to other pre-existing immunologic or genetic
factors that predispose to recurrent infections or wheez-
ing.1,2,28-33This suggestion is supported by experimental
with high IgE levels, blood eosinophilia, or increased ex-
pired nitric oxide had more severe lower respiratory tract
ical, because immature immune responses may be modi-
fied by environmental factors, such as viral infections.
This suggestion derived from a neonatal mouse model
agrees with our finding that young age at the first episode
of wheezing was associated with an increased risk for
Our results on traditional risk factors for recurrent
wheezing agree with previous studies.1,37Atopy and ma-
ternal asthma are strong predictors of persistent wheezing,
FIG 2. Probability of recurrent wheezing in prednisolone (bold line) and placebo recipients during a 1-year
follow-up (censored cases marked with vertical lines).
J ALLERGY CLIN IMMUNOL
VOLUME 119, NUMBER 3
Lehtinen et al 573
Asthma diagnosis and
whereas prematurity is more likely to be associated with
transient wheezing in early life. Both these wheezing phe-
notypes were represented in our study because the partic-
ipants were recruited from the general population, not
from a specific risk population.
An unexpected and provocative finding was that a 3-
day prednisolone treatment for the first episode of wheez-
ing associated with rhinovirus infection showed benefit
for as long as 12 months. In the rhinovirus group, 50% of
placebo recipients had at least 2 recurrences, compared
with 26% among prednisolone recipients. This finding
is in agreement with our previous report of a 2-month
follow-up.20Contrary to our finding, no disease-modify-
ing effect was seen in 2 recent studies using inhaled corti-
costeroid therapy either intermittently during wheezing in
infants or continuously in children with a positive asthma-
predictive index.38,39It is, however, important to note that
the study by Guilbert et al39included children who had
experienced recurrent wheezing episodes, making their
population very different from ours. The reasons for the
discrepancy between our study and these earlier studies
may lie in our systemic administration and higher dosage
of corticosteroids. Thus, our finding suggests that early
wheezing associated with rhinovirus is not only an impor-
tant risk factor for recurrent wheezing but also might be a
criterion for the selection of young children who arelikely
to respond to systemic corticosteroids.
We also found children with eczema to benefit from
prednisolone, which is understandable, because atopic
eczema is one of the main risk factors for asthma, and
nonatopic eczema predicts sensitization in wheezing
children.1,40Recently, Bisgaard et al38found no interac-
tion between response to intermittent inhaled corticoste-
roid therapy and eczema in infants. The treatment was
started after a 3-day episode of wheezing in an outpatient
setting. Their findings, however, do not necessarily over-
ride our results. As they suggested, higher doses and ear-
lier timing of treatment may be necessary. The efficacy of
systemic corticosteroids in children with eczema is impor-
tant to be confirmed by others, because eczema diagnosis
would be a useful clinical tool to identify wheezing chil-
dren who respond to corticosteroids.
Our finding that heterogenous group of RSV/rhino-
virus-negative children had increased tendency for re-
current wheezing compared with RSV-positive children
is in agreement with the Tucson Children’s Respiratory
Study.9They reported that at the age 13 years, there still
was a significant link between bronchiolitis and asthma
in the groups of children with virus other than RSV or
with negative microbiology. However, it is possible that
they missed many rhinovirus infections because rhinovi-
rus PCR techniques were not used. Future studies should
incorporate comprehensive microbiologic diagnostics to
elucidate better the risk related to non-RSV/nonrhinovirus
The study population was small. We studied only hospi-
talized children and had no nonwheezing children as a
control group. The inclusion criteria for the long-term
follow-up were first planned during the efficacy trial, and
thus no stratified randomization was performed. There-
fore, we regarded prednisolone versus placebo treatment
as an equal covariate to risk factors such as maternal
asthma. Our viral grouping can be criticized, although it is
in line with that of the Childhood Origins of Asthma
ing. In the regression model, we used the RSV group as
a reference group because the probability of recurrent
wheezing associated with RSV is well known. To avoid
multiple testing and consequent false-positive results, we
performed interaction tests instead of testing subgroups,
for which we provided only estimates with CIs.41Al-
ing outpatient visit or hospitalization, we cannot assure
that previous viral infections had not induced lower res-
piratory symptoms insufficient to result in noticeable
wheezing. Prolonged coughing alone can be the dominant
symptom under such circumstances. The strengths of
this study are careful recording of risk factors, detailed vi-
ral diagnostics, prospective follow-up, good adherence of
study participants, and use of the general population.
risk factor for recurrent wheezing. Furthermore, our data
suggest that prednisolone may have long-term beneficial
effects in young wheezing children affected by rhinovirus
infection. The presence of eczema may also influence
the response to prednisolone. A prospectively designed
clinical trial appropriately powered is needed to test the
hypothesis that prednisolone reduces recurrent wheezing
associated with rhinovirus infection or eczema.
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