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One-Year Follow-Up of Young Children Hospitalized for

Wheezing: The Influence of Early Anti-Inflammatory


Therapy and Risk Factors for Subsequent Wheezing
and Asthma
Tiina M. Reijonen, MD,* and Matti Korppi, MD
Summary. We investigated the 1-year outcome of children hospitalized for wheezing, paying
special attention to the effect of early anti-inflammatory therapy. In addition, we identified risk
factors for recurrent wheezing and asthma. Eighty-eight children under 2 years old treated in the
hospital for wheezing were followed for 1 year. Nebulized anti-inflammatory therapy was given
for 16 weeks: 31 patients received budesonide, 29 patients cromolyn sodium, and 28 control
patients received no therapy. The number of subsequent physician-diagnosed wheezing epi-
sodes was recorded.
Four months of anti-inflammatory therapy did not significantly decrease the occurrence of
asthma 1 year later; 45% of patients in the cromolyn group, 42% in the budesonide group, and
61% in the control group had asthma, defined as at least two bronchial obstruction episodes
during the 1-year period after the original hospitalization for wheezing. An age over 12 months
at the time of the initial bronchial obstructing episode [P = 0.009, risk ratio (RR) = 5.4, 95%
confidence interval (CI) = 1.5319.31], failure to identify a viral cause (P = 0.0003, RR = 12.0,
CI = 3.1645.40), history of wheezing (P = 0.02, RR = 14.6, CI = 1.59132.10), the presence of
atopy (P = 0.01, RR = 5.3, CI = 1.4719.21), a family history of atopy (P = 0.03, RR = 3.6, CI
= 1.1511.12), and serum eosinophil cationic protein (ECP) 16 g/L (P = 0.005) were sig-
nificant risk factors for asthma. We conclude that early anti-inflammatory therapy for 4 months
does not significantly decrease the occurrence of asthma during the period of 1 year following
hospitalization for the original episode of wheezing. Young children requiring hospital admission
for wheezing during a respiratory tract infection are at increased risk of having subsequent
asthma if they have wheezed previously, if they have atopy or a family history of atopy, if they
have elevated serum ECP, if they are over 12 months of age at the original bronchial obstructive
episode, and especially when viral studies are negative. Pediatr Pulmonol. 1998; 26:113119.
1998 Wiley-Liss, Inc.
Key words: asthma; atopy; bronchiolitis; bronchial obstruction; budesonide;
cromolyn sodium; eosinophils; eosinophil cationic protein;
immunoglobulin E; wheezing; viral infection; randomized controlled trial.
INTRODUCTION
Infants and young children with wheezing associated
respiratory tract infections are frequent patients in pedi-
atric departments. Many of these patients have a ten-
dency to wheeze after their initial infection.
13
Young
wheezing children seem to represent a heterogeneous
group of conditions which are often clinically indistin-
guishable. Some have narrow airways and their lung
function is subnormal before any respiratory illnesses
occur, and some, especially atopic children, may have
early childhood asthma.
46
Respiratory infections cause
edema and mucus production and thus obstruct small
airways.
7
The exact role of viral infections in the devel-
opment of asthma is not clear. Many studies have shown
that bronchiolitis leading to hospitalization is an impor-
tant risk factor for asthma.
2,3,8
The identification of
young children who are at risk of having recurrent
wheezing episodes or asthma after acute wheezing has
stopped is important. Based on our recent observations,
Department of Pediatrics, Kuopio University Hospital, Finland.
Presented in part at The Annual Meeting of the European Academy of
Allergology and Clinical Immunology EAACI 97, Rhodes, Hellas,
Greece June 15, 1997.
Contract grant sponsor: Foundation of Pediatric Research in Finland;
Contract grant sponsor: North Karelia Cultural Foundation; Contract
grant sponsor: University of Kuopio.
*Correspondence to: Dr. Tiina M. Reijonen, Department of Pediatrics,
Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Fin-
land.
Received 17 July 1997; accepted 9 April 1998.
Pediatric Pulmonology 26:113119 (1998)
1998 Wiley-Liss, Inc.
early anti-inflammatory therapy with cromolyn sodium
or budesonide reduces wheezing after bronchiolitis.
9
It is
not known, however, whether the early anti-inflam-
matory therapy protects the children from recurrent
wheezing episodes or decreases the prevalence of later
asthma.
The aim of this study was to investigate the 1-year
follow-up of children hospitalized for wheezing, paying
special attention to the influence of early anti-inflam-
matory therapy. In addition, we identified risk factors for
the recurrence of wheezing episodes and asthma.
MATERIALS AND METHODS
One hundred children younger than 24 months old
(median age, 10.0 months; range, 123 months) and
treated in the hospital and the Department of Pediatrics,
Kuopio University Hospital, Kuopio, Finland for wheez-
ing between January 1, 1992, and November 2, 1993,
were enrolled in the study. The clinical criteria for the
enrollment were the presence of wheezing and respira-
tory distress, leading to hospital admission during an
acute respiratory tract infection. The clinical diagnosis of
acute bronchiolitis was used.
3
Wheezing and respiratory
distress were noted on inspection and auscultation, first
by the physician on duty in the emergency room and
confirmed within 1 hour by one of the investigators. Pa-
tients were excluded when they had a history of chronic
cardiorespiratory disease, including doctor-diagnosed
asthma, or if they had received regular medication for
any pulmonary disease. After an initial clinical evalua-
tion, the patients were randomly assigned to three groups
by picking an envelope: cromolyn group; budesonide
group; or control group. The patients with and without a
history of wheezing were randomized separately. To
minimize imbalance between groups over time, a prede-
termined block randomization scheme was used, with
block sizes of 15. The wheezing episode that led to hos-
pitalization was the first episode in 87 of the children,
and the median duration of tachypnea before admission
was 1 day (range, 17 days).
Nebulized anti-inflammatory therapy was given for 16
weeks: 34 patients received cromolyn sodium, 34 budes-
onide, and 32 control patients received no anti-
inflammatory therapy. The maintenance medication was
administered by a foot-pump powered nebulizer with a
face mask (Easy-Air Nebuliser, Cameron-Price, Bir-
mingham, England), and it was started during the second
day of hospitalization. For the first 8 weeks, the dose of
cromolyn sodium (Lomudal inhalation liquid, 10 mg/
ml, Fisons Corp., Rochester, NY) was 20 mg four times
a day, and that of budesonide (Pulmicort inhalation liq-
uid, 250 g/ml, Astra, Sodertalje, Sweden) was 500 g
two times a day. For the second 8-week period the doses
were reduced: cromolyn sodium to 20 mg three times a
day and budesonide to 250 g twice a day. If additional
maintenance therapy was needed during the 16-week pe-
riod, oral slow-release theophylline was recommended.
The outcome from that 4-month period has been recently
described in detail.
9
After the termination of the early
anti-inflammatory therapy, maintenance therapy for
asthma was initiated based on clinical criteria. The study
was approved by the Research Ethics Committee of Kuo-
pio University Hospital. Before enrollment of the pa-
tients, informed oral consent was obtained from the par-
ents.
If the patients required medical attention and/or treat-
ment because of respiratory distress or wheezing, the
physicians on duty were asked to record their findings on
diary cards. The patients visited the outpatient clinic 1.5,
4, 8, and 12 months after the index episode of wheezing.
One of the two authors (T.R.) examined the children,
interviewed the parents using standard questionnaires,
and checked the diaries. The control visits were not per-
formed in a blind manner, i.e, the investigator knew to
which of the three treatment groups the patient belonged.
Ninety-one children (median age, 18.7 months; range,
9.232.4 months) attended the 8-month, and 88 children
(median age, 22.1 months; range, 13.337.4 months) the
1-year follow-up. The baseline characteristics of the sub-
jects who were lost from the follow-up did not differ
from those of the original study group.
A standardized questionnaire was used to interview
the parents. It included questions on age, history of
wheezing, atopic dermatitis, and family history of asthma
and atopic diseases. Only physician diagnoses were con-
sidered. Additional information about passive smoking
exposure, pet contacts in the home or at day care, and the
number of siblings was recorded.
Viral infections were studied by antigen detection in
the nasopharyngeal aspirates (NPA) taken at entry and by
antibody measurements in paired sera; adeno, influenza
A and B, parainfluenza types 1, 2 and 3, and respiratory
syncytial viruses (RSV) were looked for.
10
Viral antigens
were determined by time-resolved fluoroimmuno-
assay, and viral antibodies by complement fixation
tests.
10
Our test panel did not cover rhinoviruses. Thirty-
Abbreviations
CI Confidence interval
ECP Eosinophil cationic protein
IgE Immunoglobulin E
NPA Nasopharyngeal aspirate
RR Risk ratio
RSV Respiratory syncytial virus
114 Reijonen and Korppi
four (39%) of the 88 patients were virus positive; RSV
was found in 24 patients, adenoviruses in 5 patients, and
parainfluenza 3 in 9, parainfluenza 2 in one, and parain-
fluenza 1 virus in one patient. Five patients had two or
three viral findings. Viruses were evenly distributed
among the therapy groups (Table 1). During the primary
hospitalization a venous blood sample was obtained to
determine blood eosinophils, serum eosinophil cationic
protein (ECP), and immunoglobulin E (IgE). Values of
greater than 0.45 cells 10
9
/L for blood eosinophils,
11
>16 g/L for serum ECP,
10,12
>60 kU/L (144 g/L) for
serum IgE were considered significantly elevated.
13
The
ECP concentrations in the NPA were determined accord-
ing to the instructions of the manufacturer (Pharmacia
ECP RIA, Pharmacia, Uppsala, Sweden). The result was
expressed as nanograms of ECP per gram of NPA; values
of >870 ng/g were considered abnormally elevated.
14
Clinical Definitions
One or more consecutive days of wheezing followed
or preceded by a healthy period of at least 1 week con-
stituted one wheezing episode. Recurrent wheezing epi-
sodes were defined as one physician-diagnosed episode
of bronchial obstruction after the index episode. Patients
having at least two episodes of physician-diagnosed
wheezing after the index episode of wheezing were con-
sidered as having asthma.
8
Children with a history of
atopic dermatitis or an elevated level of IgE at entry were
defined as having atopy. Only physician-diagnosed cases
were included.
Statistical Analysis
Data were analyzed with the use of SPSS/PC + 5.0.1
software (SPSS Inc., Chicago, IL). Comparability among
the groups was assessed with the Chi-squared test for
proportions. The proportional differences between the
three groups were analyzed first, with the use of an over-
all Chi-square test. If the P value was <0.05, further
paired analyses were made. Two-tailed tests and a Bon-
ferroni correction
15
were used in all paired analysis. As
the distribution of age was not normal, Kruskal-Wallis
one-way analysis of variance was used in comparison of
age among the three groups. The results are expressed as
medians and ranges. The logistic regression model was
used to calculate the adjusted risk ratios (RR) with 95%
confidence intervals (CI) for estimating the associations
between potential risk factors and asthma.
RESULTS
The demographic, laboratory, and clinical characteris-
tics were similar in the three treatment groups with the
exceptions of family size and blood eosinophils (Table
1). In the budesonide group, there were more frequently
two or more siblings compared with the control group. In
addition, the cromolyn group had less frequently elevated
blood eosinophils than the other two groups.
The total follow-up period after the index episodes of
wheezing was 12 months; randomized regular early anti-
inflammatory therapy was given during the first 4
months, and anti-inflammatory therapy for asthma was
offered on the basis of clinical indications during the
TABLE 1Characteristics of 88 Young Children Admitted to Hospital for Wheezing
a
Characteristic
Cromolyn
group (n 29)
Budesonide
group (n 31)
Control
group (n 28) P
Median age (range), months 10.3 (1.022.1) 9.9 (1.623.1) 10.5 (2.123.2) 0.97
Age, <12 mo/12 mo (%) 19 (66)/10 (34) 20 (65)/11 (35) 19 (68)/9 (32) 0.96
Gender, M/F (%) 18 (62)/11 (38) 21 (68)/10 (32) 24 (86)/4 (14) 0.31
History of wheezing (%) 5/29 (17) 5/31 (16) 3/28 (11) 0.76
Atopic dermatitis at entry (%) 9/29 (31) 6/31 (19) 10/28 (36) 0.35
Serum IgE > 60 kU/L (%) 8/29 (28) 6/31 (21) 6/27 (22) 0.83
Atopy (%) 13/29 (45) 10/31 (32) 11/28 (39) 0.60
Family history of atopy (%) 14/29 (48) 20/31 (65) 13/28 (46) 0.30
Family history of asthma (%) 6/29 (21) 9/31 (29) 5/28 (18) 0.56
Passive smoking (%) 14/29 (48) 16/31 (51) 11/28 (39) 0.62
A pet at home or at day care (%) 8/29 (28) 10/31 (32) 10/28 (36) 0.80
Two or more siblings (%) 10/29 (34) 17/31 (55)* 6/28 (21) 0.03
Positive viral identification (%) 11/29 (38) 13/31 (42) 10/28 (36) 0.88
Blood eosinophils 0.45 10
9
/L (%) 4/29 (14)* 11/29 (38) 13/27 (48) 0.02
Serum ECP 16 g/L (%) 3/29 (10) 3/31 (10) 10/28 (29) 0.09
Nasopharyngeal ECP 870 ng/g (%) 6/28 (21) 14/29 (14) 11/27 (41) 0.06
a
Median age determined by Kruskall-Wallis one-way analysis of variance. , atopic dermatitis or serum IgE 60 KU/L
at entry; , atopic dermatitis or allergic rhinitis diagnosed by physician; , positive identification of viral antigen or
significant rise in antibodies. The viruses searched for were respiratory syncytial viruses, influenza A and B, parainfluenza
types 1,2,3, and adenoviruses. IgE, immunoglobulin E; ECP, eosinophil cationic protein.
*P < 0.05 compared with the control group. P values determined by Chi-squared test.
Follow-Up of Early Childhood Wheezing 115
subsequent 8 months. During the total follow-up period,
27 of 88 patients (31%) had no subsequent physician-
diagnosed bronchial obstruction, 18 patients (21%) had
one (recurrent wheezing group), and 43 patients (49%)
had two or more bronchial obstructions (asthma group).
The proportions of children with asthma, recurrent
wheezing, or with no wheezing did not differ signifi-
cantly in the original therapy groups (Fig. 1). At the end
of the follow-up period, 8 children (28%) in the former
cromolyn group, 9 (29%) in the former budesonide
group, and 13 (48%) in the control group received main-
tenance therapy for asthma (P 0.24). Of these 30
children, 11 were given cromolyn, 12 were given budes-
onide, and 2 were given oral theophylline. Five children
received combination therapy: two patients received cro-
molyn and theophylline; two patients budesonide and
theophylline; and one patient budesonide and salmeterol.
All but two children with asthma had experienced at least
one subsequent episode of wheezing after the first 4-
month period.
Of the 88 children, 34 (39%) who completed the 1-
year follow-up had positive viral identification during the
index episode of wheezing. These 34 children had sig-
nificantly less asthma and were significantly more often
without symptoms during the follow-up than the 54 pa-
tients with no viral identification (Fig. 2).
We evaluated the potential risk factors for subsequent
wheezing by comparing the characteristics of patients
with no subsequent bronchial obstruction to the charac-
teristics of those with recurrent wheezing episode and to
those with asthma. An age of more than 12 months at the
time of the original (baseline) airway obstructive episode
was a significant risk factor for asthma (P 0.009, risk
ratio, RR 5.4, 95% confidence interval CI 1.53
19.31). Only 4 of 27 children (15%) with no subsequent
episodes of wheezing were older than 12 months of age
at the start of the study. The 4 months of anti-
inflammatory therapy either with cromolyn sodium or
with budesonide did not significantly diminish the risk of
asthma (Fig. 1) When calculating the effects of other risk
factors, both of these factors (age as a significant and
anti-inflammatory therapy as a possible confounding fac-
tor) were adjusted for. The absence of viral identification
was the dominant risk factor for asthma (Table 2). The
result was the same for the patients with negative RSV
identification (P 0.001, RR 11.9, CI 2.72
52.30). Other significant risk factors for asthma were
history of wheezing, the presence of atopy at entry, and
family history of atopy. The following factors did not
predict the development of asthma: male gender, atopic
dermatitis, family history of asthma, passive smoking, or
pet contacts at home or at day care, having two or more
siblings, or the presence of elevated blood eosinophils,
serum IgE, or nasopharyngeal ECP. The significant risk
factors for the recurrence of wheezing were atopic der-
matitis (P 0.04, RR 5.8, 95% CI 1.06 2.0),
atopy (P 0.047, RR 5.3, 95% CI 1.0227.92 ),
family history of atopy (P 0.02, RR 7.4, 95% CI
1.4537.56), and having two or more siblings (P
0.007, RR 10.2, 95% CI 1.8755.55). No other risk
factor was significant in relation to the recurrence of
wheezing. Because none of the 27 subsequently non-
wheezing patients had serum ECP 16 g/L, the risk
ratios for asthma and recurrent wheezing were incalcu-
lable. As many as 11 of 43 patients (26%) in the asthma
group (P 0.005 vs. nonwheezing children) and 3 of 18
patients (17%) in the recurrent wheezing group (P
0.06 vs. nonwheezing children) had serum ECP 16
g/L. Thus, serum ECP 16 g/L is considered as a
significant risk factor for asthma.
Fig. 1. The outcome of 88 young children in three therapy
groups 1 year after hospitalization for wheezing. The differ-
ences among the groups were not significant.
Fig. 2. The outcome of 88 young children according to viral
identification at entry 1 year after hospitalization for wheezing
*** P = 0.0002 compared with the virus-negative children with
asthma, ****P = 0.00001 compared with the virus-negative chil-
dren with no wheezing (Chi-squared test).
116 Reijonen and Korppi
DISCUSSION
This prospective, controlled study in children treated
in hospital for wheezing shows that early anti-inflam-
matory therapy for 4 months does not significantly de-
crease the occurrence of asthma 1 year later. Asthma was
defined in a very strict way as two physician-diagnosed
episodes of wheezing after the index episode. The other
purpose of this study was to find clinically useful criteria
for predicting which children are at risk to have recurrent
episodes of wheezing or asthma. Only a minority (about
1%) of young children need hospital treatment for bron-
chial obstruction.
16
This study was hospital-based, and
thus the patients represented severe cases. In the present
study, age over 12 months at the time of the initial (in-
dex) episode of wheezing, absence of viral identification,
history of wheezing, presence of atopy, family history of
atopy, and elevated serum ECP were identified as sig-
nificant risk factors for asthma. A recent study by Young
and colleagues showed that lower respiratory illness la-
beled as bronchiolitis in the second year is likely to be
asthma.
6
Our observation that wheezing children older
than 12 months had a significantly higher risk for asthma
than the younger ones supports that view. In fact, only
15% of patients with no subsequent wheezing episodes
were at entry older than 12 months.
Our recent study showed that early anti-inflammatory
therapy of bronchiolitis with nebulized cromolyn sodium
or budesonide for 4 months reduced wheezing after bron-
chiolitis.
9
The present study showed that this initial ben-
eficial effect did not persist when therapy was stopped
and recurrent wheezing episodes or asthma did not differ
significantly among the patients who had received early
anti-inflammatory therapy and those who had not. Only
18% of the patients who had not received early anti-
inflammatory therapy did not wheeze during the follow-
up period of 1 year. The respective figure was 41% in
patients who had received cromolyn sodium and 32% in
the patients who had received budesonide as early anti-
inflammatory therapy. These findings suggest that early
anti-inflammatory therapy may have some prolonged ef-
fect in protecting subsequent bronchial obstructions. Be-
cause the occurrence of asthma was significantly depen-
dent on the age of the children, and because the early
anti-inflammatory therapy was a possible confounding
factor, both of these factors were controlled in the analy-
sis of the other risk factors.
The significantly lower risk for asthma in patients with
a demonstrable viral identification compared with those
with no established viral identification was one of the
most interesting findings of this study. The outcome did
not depend on the type of viral infection looked for; the
risk for asthma was the same in patients with RSV as in
those with other viral infections. This result is different
from a previous study with a rather similar patient
group.
17
In that study, the outcome of children with ob-
structive bronchitis did not differ in patients with and
without established RSV infection. Despite negative vi-
rologic results, all our wheezing patients with a high
probability for asthma had an infection; the presence of
symptoms consistent with acute respiratory tract infec-
tion was one of the inclusion criteria of the study. Thus,
it is likely that the virus-negative children had the first
manifestation of asthma and started to wheeze as a result
of mild upper respiratory tract infection or as a result of
TABLE 2Age- and Anti-inflammatory Therapy-Adjusted Risk Factors for Asthma in 70
Children 1 Year after Bronchiolitis
a
Risk Factor
Asthma
(n 43)
No wheezing
(n 27) P
Significance
RR 95% CI
No viral identification 35/43 (81%) 8/27 (30%) 0.0003 12.0 3.1645.40
History of wheezing 12/43 (28%) 1/27 (4%) 0.02 14.6 1.59132.10
Atopic dermatitis at entry 16/43 (37%) 3/27 (11%) 0.09 3.5 0.8414.70
Serum IgE 60 kU/L) 14/42 (33%) 2/25 (8%) 0.06 5.0 0.9227.93
Atopy 23/43 (53%) 4/27 (15%) 0.01 5.3 1.4719.21
Family history of atopy 26/43 (60%) 9/27 (33%) 0.03 3.6 1.1511.12
Family history of asthma 9/43 (21%) 7/27 (26%) 0.29 0.5 0.131.84
Male gender 35/43 (81%) 18/27 (67%) 0.23 2.3 0.608.56
Passive smoking 22/43 (51%) 14/27 (52%) 0.82 1.1 0.393.25
A pet at home or at day care 11/43 (26%) 9/27 (33%) 0.67 0.8 0.252.46
At least two siblings 13/43 (30%) 8/27 (30%) 0.71 1.3 0.384.15
Blood eosinophils 0.45 10
9
/L 17/42 (40%) 4/26 (15%) 0.23 2.3 0.589.17
Nasopharyngeal ECP 870 ng/g 12/39 (31%) 4/27 (15%) 0.56 1.5 0.376.29
a
P values, RR (risk ratio), and 95% CI (confidence interval) were determined by logistic regression
adjusted for age and anti-inflammatory therapy. Analyses have been done separately for each risk factor.
, positive identification of viral antigen or significant rise in antibodies. The viruses searched for were
respiratory syncytial viruses, influenza A and B, parainfluenza types 1,2,3, and adenoviruses. , atopic
dermatitis or serum IgE 60 KU/L at entry; , atopic dermatitis or allergic rhinitis diagnosed by
physician; IgE, immunoglobulin E; ECP, eosinophil cationic protein.
Follow-Up of Early Childhood Wheezing 117
viruses we did not study, such as rhino- or corona vi-
ruses. The influence of rhinoviruses on the outcome after
early childhood wheezing need further studies. Our re-
sults support the theory that viral or other infections, or
the airway damage caused by them, have a minor role in
the development of asthma.
18
Our observation that a history of wheezing is an im-
portant risk factor for asthma is consistent with previous
findings.
8,19
In our 1-year follow-up, 12 of the 13 chil-
dren (92%) with a history of wheezing developed
asthma, and only one (8%) had no subsequent wheezing.
In accordance with some previous studies, children who
have atopy
5,9,19
or family history of atopy
20,21
were
prone to recurrent wheezing and asthma. Contrary to pre-
vious observations of population based studies, male
gender
21,22
family history of asthma
5,23
or passive smok-
ing
2124
were not significant risk factors for recurrent
wheezing or asthma. The result that there was no rela-
tionship between passive smoking and asthma was sur-
prising; this observation may be true, because many par-
ents now smoke outdoors. It is also possible that smoking
did not emerge as a risk factor because it was so frequent
in the population as a whole. Likewise, the development
of asthma did not depend on contact with pets.
8
The
observation that having two or more siblings was a sig-
nificant risk factor for recurrent wheezing can be ex-
plained by increased number of contacts with infections
in these families.
In this study,
20
elevated blood eosinophil counts were
not a risk factor for recurrent wheezing or asthma, which
is consistent with previous observations. Our recent re-
ports showed that high concentrations of serum
10
and
nasopharyngeal ECP
14
were predictive of bronchial ob-
structions, and especially of episodes requiring hospital
treatment. This study confirmed that elevated concentra-
tion of serum ECP significantly predicted asthma. In fact,
all of the 14 patients with elevated serum ECP at entry
had at least one subsequent physician-diagnosed bron-
chial obstruction, and 11 (79%) had asthma 1 year later.
The high concentration of ECP in respiratory secretions
did not, however, associate with the occurrence of recur-
rent wheezing or asthma in this follow-up.
The term asthma has been rarely used to describe
recurrent or persistent wheezing in the very young. The
reasons for this are the differences in outcome, and pos-
sibly differences in pathophysiology between young chil-
dren and those at school age.
46,25
Although the majority
of children with early childhood wheezing will grow out
of their symptoms,
5,19
an important problem remains
how to reduce bronchial obstructions and hospital admis-
sions in early childhood. The avoidance of the term
asthma will lead to inappropriate treatment with an-
tibiotics
26
instead of bronchodilator
2729
and anti-
inflammatory agents.
9,30,31
On the basis of previous stud-
ies, the persistence of asthma in late childhood can be
decreased by diminishing exposure to inhaled allergens
32
and to tobacco smoke.
33
The influence of an early intro-
duction of anti-inflammatory therapy on the posttreat-
ment outcome in wheezing children needs further stud-
ies. Such therapy did not provide protection for 1 year in
the present study. There are three possible explanations
for the negative results. First, the number of children in
this study was too small to detect small difference (17%)
between the therapy and the control groups. The power
was calculated after the study, and it was only 0.44 at the
significance level of 0.05. Second, the treatment period
may have been too short. Third, although anti-
inflammatory therapy lessens bronchial obstruc-
tions,
9,30,31
it probably has little long-term posttreatment
effects on the lungs.
In conclusion, early anti-inflammatory therapy for 4
months does not significantly decrease the occurrence of
asthma 1 year after hospital admission for wheezing. Age
over 12 months, history of wheezing, elevated serum
ECP concentrations, atopy, or family history of atopy
increased the risk for asthma. The outcome was much
worse in the children with negative than in those with
positive viral identifications. We suggest that young chil-
dren admitted to hospital for wheezing should be re-
garded as having asthma if they have wheezed previ-
ously, if they have atopy, have a family history of atopy,
or have elevated serum ECP levels, especially if viral
identifications are negative. An age over 12 months at the
time of the original index episode supports the diagnosis.
ACKNOWLEDGMENTS
The authors thank Pirjo Halonen, PhD, for her advice
with the statistical analyses, and the Foundation of Pe-
diatric Research in Finland, the North Karelia Cultural
Foundation, and the University of Kuopio for financial
support.
REFERENCES
1. Henry RL, Hodges IGC, Milner AD, Stokes GM. Respiratory
problems 2 years after acute bronchiolitis in infancy. Arch Dis
Child. 1983; 58:713716.
2. Murray M, Webb MSC, OCallaghan C, Swarbrick AS, Milner A.
Respiratory status and allergy after bronchiolitis. Arch Dis Child.
1992; 67:482487.
3. Korppi M, Reijonen T, Poysa L, Juntunen-Backman K. A 2-year
to 3-year outcome after bronchiolitis. Am J Dis Child. 1993; 147:
628631.
4. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM.
Diminish lung function as a predisposing factor for wheezing
illness in infants. N Engl J Med. 1988; 319:11121117.
5. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M,
Morgan WJ. Asthma and wheezing in the first six years of life. N
Engl J Med. 1995; 332:133137.
6. Young S, OKeeffe PT, Arnott J, Landau LI. Lung function, air-
118 Reijonen and Korppi
way responsiveness, and respiratory symptoms before and after
bronchiolitis. Arch Dis Child. 1995; 72:1624.
7. Wohl MEB, Chernick V. State of art: Bronchiolitis. Am Rev
Respir Dis. 1978; 53:707709.
8. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B.
Asthma and immunoglobulin E antibodies after respiratory syn-
cytial virus bronchiolitis: A prospective study with matched con-
trols. Pediatrics. 1995; 95:500505.
9. Reijonen T, Korppi M, Kuikka L, Remes K. Anti-inflammatory
therapy reduces wheezing after bronchiolitis. Arch Pediatr Ado-
lesc Med. 1996; 150:512517.
10. Reijonen TM, Korppi M, Kuikka L, Savolainen K, Kleemola M,
Mononen I, Remes K. Serum eosinophil cationic protein as a
predictor of wheezing after bronchiolitis. Pediatr Pulmonol. 1997;
23:397403.
11. Eisen A. Eosinophilia. In: Bierman CW, Pearlman DS eds. Aller-
gic Diseases in Infancy, Childhood and Adolescence. 1st ed.
Philadelphia: WB Saunders, 1980:761762.
12. Peterson CGB, Enander I, Nystrand J, Anderson AS, Nilsson L,
Venge P. Radioimmunoassay of human eosinophil cationic pro-
tein (ECP) by an improved method. Establishment of normal lev-
els in serum and turnover in vivo. Clin Exp Allergy. 1991; 21:
561567.
13. Saarinen UM, Juntunen K, Kajosaari M, Bjorksten F. Serum im-
munoglobulin E in atopic and non-atopic children aged 6 months
to 5 years. Acta Pediatr Scand. 1982; 71:489494.
14. Reijonen TM, Korppi M, Kleemola M, Savolainen K, Kuikka L,
Mononen I, Remes K. Nasopharyngeal eosinophil cationic protein
in bronchiolitis: Relation to viral findings and subsequent wheez-
ing. Pediatr Pulmonol. 1997; 24:3541.
15. Zar JH. Biostatistical Analysis, 2nd ed. Englewood Cliffs: Pren-
tice-Hall Inc, 1984:402403.
16. Phelan PD, Landau LI, Olinsky A. Respiratory illness in children.
Oxford: Blackwell, 1990:6673.
17. Wennergren G, Hansson S, Engstrom I, Jodal U, mark M, Brolin
I, Juto P. Characteristics and prognosis of hospital-treated obstruc-
tive bronchitis in children aged less than two years. Acta Paediatr.
1992; 81:4045.
18. Martinez FD. Viral infections and the development of asthma. Am
J Respir Crit Care Med. 1995; 151:16441648.
19. Korppi M, Kuikka L, Reijonen T, Remes K, Juntunen-Backman
K, Launiala K. Bronchial asthma and hyperreactivity after early
childhood bronchiolitis and pneumonia, an 8-year follow-up
study. Arch Pediatr Adolesc Med. 1994; 148:10791084.
20. Zweiman B, Schoenwetter WF, Hildreth EA. The relationship
between bronchiolitis and allergic asthma. J Allergy. 1966; 37:
4853.
21. Arshad SH, Stevens M, Hide DW. The effect of genetic and
environmental factors on the prevalence of allergic disorders at the
age of two years. Clin Exp Allergy. 1993; 23:504511.
22. Halken S, Host A, Husby S, Hansen LG, Osterballe O, Nyboe J.
Recurrent wheezing in relation to environmental risk factors in
infancy. Allergy. 1991; 46:507514.
23. Lindfors A, Wickman M, Hedlin G, Pershagen G, Rietz H, Nor-
dvall SL. Indoor environmental risk factors in young asthmatics:
A case-control study. Arch Dis Child. 1995; 73:408412.
24. Holberg CJ, Wright AL, Martinez FD, Morgan WJ, Taussig LM.
Child day care, smoking by caregivers, and lower respiratory tract
illness in the first 3 years of life. Pediatrics. 1993; 91:885892.
25. Stick SM, Arnott J, Turner DJ, Young S, Landau LI, Lesouef PN.
Bronchial responsiveness and lung function in recurrently wheezy
infants. Am Rev Respir Dis. 1991; 144:10121015.
26. Speicht ANP, Lee DA, Hey EN. Under-diagnosis and under-
treatment of asthma in childhood. BMJ. 1983; 286:12531256.
27. Schuh S, Canny G, Reisman JJ, Kerem E, Bentur L, Petric M,
Levison H. Nebulized albuterol in acute bronchiolitis. J Pediatr.
1990; 117:633637.
28. Klassen TP, Rowe PC, Sutcliffe T, Ropp LJ, McDowell IW, Li
MM. Randomized trial of salbutamol in acute bronchiolitis. J
Pediatr. 1991; 118:807811.
29. Reijonen T, Korppi M, Pitkakangas S, Tenhola S, Remes K. The
clinical efficacy of nebulized racemic epinephrine and albuterol in
acute bronchiolitis. Arch Pediatr Adolesc Med. 1995; 149:686
692.
30. Carlsen KH, Leegaard J, Larsen S, Orstavik I. Nebulised beclo-
methasone dipropionate in recurrent obstructive episodes after
bronchiolitis. Arch Dis Child. 1988; 63:14821433.
31. De Blic J, Delacourt C, Le Bourgeois M, Mahut B, Ostinelli J,
Caswell C, Scheinmann P. Efficacy of nebulized budesonide in
treatment of severe infantile asthma: A double blind study. J Al-
lergy Clin Immunol. 1996; 98:1420.
32. Morgan WJ, Martinez FD. Risk factors for developing wheezing
and asthma in childhood. Pediatr Clin North Am. 1992; 39:1185
1203.
33. Martinez FD, Antognoni G, Macri F, Bonci E, Midulla F, De
Castro G, Ronchetti R. Parental smoking enhances bronchial re-
sponsiveness in nine-year-old children. Am Rev Respir Dis. 1988;
138:518523.
Follow-Up of Early Childhood Wheezing 119