Pediatric Allergy and Immunology

ORIGINAL ARTICLE Asthma

Low eosinophils during bronchiolitis in infancy are

associated with lower risk of adulthood asthma
Katri Backman1, Kirsi Nuolivirta2, Hertta Ollikainen3, Matti Korppi4 & Eija Piippo-Savolainen1
1
Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland; 2Sein€ €joki, Finland; 3University of Eastern
ajoki Central Hospital, Seina
Finland, Kuopio, Finland; 4Center for Child Research, Tampere University and University Hospital, Tampere, Finland

To cite this article: Backman K, Nuolivirta K, Ollikainen H, Korppi M, Piippo-Savolainen E. Low eosinophils during bronchiolitis in infancy are associated with lower risk
of adulthood asthma. Pediatr Allergy Immunol 2015: 26: 668–673.

Keywords Abstract
asthma; bronchiolitis; eosinophils; respiratory
syncytial virus
Background: Infant bronchiolitis may be the first manifestation of asthma.
Aim: To evaluate the association of early-childhood risk or protective factors for
Correspondence asthma and lung function reduction in adults 30 years after bronchiolitis in infancy.
Kirsi Nuolivirta, Department of Pediatrics, Methods: Forty-seven former bronchiolitis patients attended the clinical study at the
Sein€ajoki Central Hospital, Hanneksenrinne median age of 29.5 years, including doctoral examination and measurement of post-
7, 60220 Sein€ ajoki, Finland bronchodilator lung function with flow-volume spirometry. Data on early-life risk
Tel.: +358-6-4154111 factors including blood eosinophil counts on admission for bronchiolitis and on
Fax: +358-6-4154963 convalescence 4–6 weeks after bronchiolitis were available.
E-mail: kirsi.nuolivirta@fimnet.fi Results: Low blood eosinophil count <0.25 9 10E9/l on admission for bronchiolitis
was a significant protective factor and high blood eosinophil count >0.45 9 10E9/l on
Accepted for publication 12 July 2015 convalescence was a significant risk factor for asthma in adulthood independently
from atopic status in infancy. Parental asthma and high blood eosinophil count
DOI:10.1111/pai.12448 >0.45 9 10E9/l during bronchiolitis were significant risk factors for irreversible airway
obstruction (FEV1/FVC ratio below the 5th percentile lower limit of normality after
bronchodilation).
Conclusion: Our adjusted analyses confirmed that eosinopenia during infant bronchi-
olitis predicted low asthma risk and eosinophilia outside infection predicted high
asthma risk up to the age of 28–31 years. Parental asthma and eosinophilia during
bronchiolitis were recognized as risk factors for irreversible airway obstruction.

Bronchiolitis or wheezing in infancy may be the first manifes-
tation of asthma (1). Thus far, the longest post-bronchiolitis
follow-ups have continued for about 20 years (2–4). Although
most young children with wheezing seem to grow out from
their wheezing tendency before or at school age, asthma
relapses are common in young adults (1). The most consistently
found early-life risk factors for asthma in adolescents and
young adults have been family history of asthma and/or
allergy, presence of atopic dermatitis in infancy, exposure to
tobacco smoke during pregnancy or in infancy, sensitization to
seasonal allergens in early years, and repetition of wheezing by
the age of 24 months (1). Less is known about the start, causes,
and risk factors of later lung function deficits. Preliminary
evidence suggests that lung function disorders, although
manifesting in adulthood, may have their origin in early
childhood (5). Irreversible lung function deficits mean that
structural changes have developed in the airways.
In our previous studies, parental asthma, repeated wheez-
ing at the age of 0–1 year and 1–2 years, and atopic
dermatitis at the age of 0–2 years were significant risk factors
for asthma in young adults who were hospitalized for
bronchiolitis at the age of <24 months (3, 6). Parental
asthma, maternal smoking, and repeated wheezing at the
age of 0–1 year were significant risk factors for reduced lung
function (3, 6). Asthma risk was lower after bronchiolitis
caused by respiratory syncytial virus (RSV) than after non-
RSV bronchiolitis (7). Low eosinophils during the convales-
cence phase after bronchiolitis were associated with less
asthma risk until late school age (8).
When this post-bronchiolitis cohort was followed for
30 years, asthma diagnoses and the use of bronchodilators
and inhaled corticosteroids (ICS) were more common in
former bronchiolitis patients than in population-based controls
(9). In line, all pre-bronchodilator (BD) and post-BD lung
function parameters were lower in former bronchiolitis patients
than in controls (10), suggesting that early-childhood bronchi-
olitis is a significant risk factor for irreversible airway
obstruction in early middle age.

668 Pediatric Allergy and Immunology 26 (2015) 668–673 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Backman et al.
The aim of this study was to evaluate the association
between early-childhood risk or protective factors and asthma
or lung function reduction in adults 30 years after bronchiolitis
in infancy. As a special focus was paid on the bronchiolitis-
related factors, such as viral findings or eosinophil responses
during infection in infancy, the use of population-based
controls was not possible, and therefore, internal controls
within the study group were used.
Patients and methods
Study subjects
In 1981–1982, altogether 83 patients were hospitalized for
bronchiolitis at the age of <24 months in the Department of
Pediatrics, Kuopio University Hospital, Finland (11). Data on
wheezing history and on potential early-life risk factors for
asthma were collected by repeated control visits until the age of
2.5 years (12). Collected data included doctor-diagnosed asthma
and allergy in mothers and fathers, parental smoking history,
presence of doctor-diagnosed atopic dermatitis in children at less
than 2 years of age, and numbers of wheezing episodes in children
registered separately for the age periods of 0–1 and 1–2 years.
Total serum immunoglobulin E (IgE) was studied at the ages of 6–
12 and 18–24 months. Viral etiology of bronchiolitis, including
respiratory syncytial virus (RSV) and 6 other respiratory viruses,
was studied with antigen detection in nasopharyngeal aspirates
on admission, and with antibody tests in paired sera obtained on
admission and 4–6 weeks later (11). Blood eosinophils were
counted on admission and on convalescence 4–6 weeks later (12).
In 2010, when the former bronchiolitis patients were 28–
31 years of age, we again performed a clinical control study
consisting of doctoral examination, 2-week home peak expira-
tory flow (PEF), monitoring and flow-volume spirometry
(FVS), and 48 (58%) former bronchiolitis patients attended
(9). FVS included both pre-BD and post-BD measurements,
and an acceptable FVS was obtained from all but one of the
study subjects (10).
Asthma and current smoking
As published recently (9), a previous doctor-settled asthma
diagnosis combined with ongoing regular maintenance medica-
tion with inhaled corticosteroids (ICS), or with asthma-pre-
sumptive symptoms, or with repeated use of bronchodilators
during the preceding 12 months, was required for the diagnosis
of self-reported asthma. In addition, study subjects with asthma-
presumptive symptoms and/or repeated use of bronchodilators
during the preceding 12 months, combined with a pathological
result in the home PEF monitoring, were included (9).
Fourteen (30%) former bronchiolitis patients were current
daily smokers (one cigarette or more smoked daily during the
preceding 12 months).
Lung function data
As published recently (10), lung function was studied
with Medikro SpiroStar USB spirometer (Medikro, Kuopio,
Pediatric Allergy and Immunology 26 (2015) 668–673 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Blood eosinophils and asthma
Finland) using Spiro 2000, software version 2.2, according to
the American Thoracic Society and European Respiratory
Society standards (13). Three or more technically acceptable
pre-BD and post-BD (15 min after inhalation of 400 lg
salbutamol, Ventoline Evohaler 0.1 mg/dose; GlaxoSmithK-
line) measurements were required, and the best pre-BD and
post-BD values were included in the analyses. We defined
irreversible airway obstruction using multiethnic, with age, sex
and height adjusted, Global Lung Function Initiative 2012
(GLI 2012) limits for abnormal FEV1/FVC ratio (14). Based
on this criterion, irreversible obstruction was considered to be
present, if post-BD FEV1/FVC ratio was below the 5th
percentile of lower limit of normality (LLN), corresponding
z-score 1.64 (FEV1/FVC <5th percentile) (14).
Statistics
Data were analyzed using SPSS 21.0 software (SPSS Inc.,
Chicago, IL, USA). The significances of the differences were
tested with logistic regression, and the results are given as odds
ratios (OR) and 95% confidence intervals (CI). All analyses
were adjusted for current daily smoking. In addition, adjust-
ments with sex and atopy in infancy were used when
appropriate. The factors included in the multivariable models
were selected based on the previously found risk and protective
factors and are presented as footnotes in the tables in question.
Ethics
The study was approved by the Ethics Committee of the
Pohjois-Savo Health-Care District. A written consent was
obtained from all study subjects.
Results
Forty-seven former bronchiolitis patients with an acceptable
FVS measurement at 28–31 years of age were the subjects of
this study. The mean age of the patients attending the study
was 29.5 years (SD 0.72), and 29 (62%) were men. Current self-
reported asthma was present in 17 (36%) study subjects.
Irreversible airway obstruction (FEV1/FVC ratio below 5th
percentile) was documented in 7 (15%) study subjects: four
with and three without current self-reported asthma. Among
the 14 current smokers, 10 had been exposed and four had not
been exposed to tobacco smoke in infancy. All analyses of this
study were performed as adjusted with current smoking.
Repeated wheezing at the age of 1–2 years and under 2 years
of age, and high eosinophil count (>0.45 9 10E9/l) on convales-
cence 4–6 weeks after bronchiolitis increased the risk of asthma,
and low eosinophil count (<0.25 9 10E9/l) during bronchiolitis
decreased the risk of asthma at the age of 28–31 years (Table 1).
Parental history of asthma and high eosinophil count on
convalescence were significant risk factors for irreversible airway
obstruction (FEV1/FVC ratio below 5th percentile) (Table 1).
Etiology of bronchiolitis (non-RSV or RSV) or presence of
atopic dermatitis or atopy (atopic dermatitis and/or serum total
IgE >60 IU/l) in infancy (Table 1) or maternal, paternal, or
parental smoking when the child was <12 months old (data not
669
Blood eosinophils and asthma Backman et al.

Table 1 Early-life risk and protective factors for asthma and irreversible bronchial obstruction at the age of 28–31 years in 47 former bronchiolitis
patients analyzed as adjusted with current smoking

Self-reported asthma* N = 17 FEV1/FVC<5th percentile† N = 7

Risk or protective factors N (%) OR (95%CI)‡ N (%) OR (95%CI)‡

Parental asthma§ (N = 7) 3 (43%) 1.78 (0.34–9.43) 3 (43%) 6.57 (1.02–42.45)

Parental atopy¶ (N = 14) 3 (21%) 0.46 (0.10–2.05) 1 (7%) 0.31 (0.03–2.86)
Repeated wheezing** at <1 year (N = 13) 5 (39%) 1.04 (0.28–3.93) 3 (23%) 1.73 (0.29–10.34)
Repeated wheezing** at 1–2 years (N = 26) 13 (50%) 4.21 (1.06–16.82) 5 (19%) 1.85 (0.31–11.03)
Repeated wheezing** at <2 years (N = 31) 15 (48%) 6.18 (1.15–33.14) 5 (16%) 1.06 (0.17–6.42)
Atopic dermatitis†† (N = 7) 4 (57%) 2.37 (0.43–13.04) 1 (14%) 1.22 (0.11–13.97)
Atopy‡‡ (N = 24) 10 (42%) 1.34 (0.39–4.65) 3 (13%) 0.68 (0.13–3.62)
Non-RSV bronchiolitis (N = 33) 11 (33%) 0.70 (0.19–2.55) 6 (18%) 2.70 (0.29–25.15)
RSV bronchiolitis (N = 14) 6 (43%) 1.43 (0.39–5.22) 1 (7%) 0.37 (0.04–3.46)
Blood eosinophils <0.25 9 109/l in admission§§ (N = 28) 6 (21%) 0.19 (0.05–0.70) 2 (7%) 0.22 (0.04–1.27)
Blood eosinophils >0.45 9 109/l in admission§§ (N = 11) 5 (46%) 1.91 (0.46–7.9) 4 (36%) 5.87 (1.04–33.29)
Blood eosinophils <0.25 9 109/l on convalescence¶¶ (N = 25) 7 (28%) 0.40 (0.11–1.41) 4 (16%) 1.45 (0.27–7.88)
Blood eosinophils >0.45 9 109/l on convalescence¶¶ (N = 9) 6 (67%) 6.07 (1.16–31.83) 2 (22%) 1.69 (0.26–10.95)

*For definition of asthma, please see the text.

†FEV1/FVC ratio below the 5th percentile lower limit of normality after bronchodilation test.
‡Odds ratio and 95% confidence interval, adjusted for current daily smoking.
§Doctor-diagnosed parental asthma present.
¶Doctor-diagnosed parental atopic dermatitis and/or hay fever present.
**More than two doctor-diagnosed wheezing episodes during the follow-up period.
††Doctor-diagnosed atopic dermatitis at the age of less than 2 years.
‡‡Doctor-diagnosed atopic dermatitis and/or high serum IgE >60 IU/l at the age of <2 years.
§§On admission to hospital for bronchiolitis.
¶¶On convalescence, 4–6 weeks after bronchiolitis.

shown) had no significant association with self-reported asthma
or irreversible airway obstruction at the age of 28–31 years.
Next, we included female gender, parental asthma, atopy in
infancy, current smoking, and repeated wheezing under 2 years
of age, in the second logistic regression, to study their indepen-
dent association with self-reported asthma or irreversible airway
obstruction. In this multivariate model, parental asthma was an
independently significant risk factor for irreversible airway
obstruction, and none of them was an independently significant
risk factor for self-reported asthma (Table 2).
All former bronchiolitis patients, who had parental asthma
as a risk factor, had repeated wheezing by the age of 2 years.
Due to interaction between them, repeated wheezing under
2 years of age (Table 2), as well as repeated wheezing at the age
of 1–2 years (Data not shown), lost their significances as
asthma risk factors in multivariable analyses.
Finally, low (<0.25 9 10E9/l) and high (>0.45 9 10E9/l)
eosinophils on admission or on convalescence were included in
the third logistic regression, adjusted for gender, current
smoking, and atopy in infancy, to study whether the associ-
ations between blood eosinophils during or outside bronchi-
olitis and asthma or irreversible airway obstruction in
adulthood are dependent on or independent from atopic status
in infancy (Table 3). Low eosinophil count (<0.25 9 10E9/l)
on admission to hospital for bronchiolitis remained as a
significant protective factor and high eosinophil count
(>0.45 9 10E9/l) on convalescence as a significant risk factor
for asthma in adulthood independently from atopic status in
infancy. In addition, high eosinophil count on admission was
an independently significant risk factor for irreversible airway
obstruction in adulthood (Table 3).
Discussion
Low eosinophil count <0.25 9 10E9/l on admission to hospital
for bronchiolitis in infancy was a significant protective factor
and high eosinophil count >0.45 9 10E9/l outside the infection
a significant risk factor for post-bronchiolitis asthma in
adulthood at the age of 28–31 years, independently from
atopic status in infancy. High eosinophils during bronchiolitis
were independently associated with irreversible airway obstruc-
tion in adulthood. Viral etiology of bronchiolitis, although
influencing the outcome until the age of 18-to-20-years (1), did
not anymore associate with asthma or defective lung function.
The finding that low blood eosinophils during bronchiolitis
were protective for post-bronchiolitis asthma in adulthood is in
line with some earlier observations, although consistent
research data are lacking (15, 16). Decrease in eosinophils
seems to be a normal response to viral infection in infants older
than 2 months of age (16, 17), maybe due to accumulation
of eosinophils in the lungs during lower respiratory infection
(18–20). In line, blood eosinophils were reduced during
bronchiolitis in those children who were about to become
transient wheezers but not in those with later permanent
wheezing in a birth cohort study (21), and high blood
eosinophils predicted the persistence of wheezing until 3 years

670 Pediatric Allergy and Immunology 26 (2015) 668–673 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Backman et al. Blood eosinophils and asthma

of age in a post-bronchiolitis study (22). In our cohort, blood olitis patients with more asthma later (8). Based on prospective
eosinophils were significantly lower during bronchiolitis than post-bronchiolitis studies (23), and on birth cohort studies (24),
outside the infection if the study subjects had not doctor- increased eosinophils outside infections are commonly
diagnosed asthma or lung function deficiency at the age of 18– accepted as risk factors for later asthma. In accordance, high
20 years (8). This finding, suggesting an eosinopenic response eosinophils on convalescence outside the infection predicted
to infection, was more evident in RSV-positive bronchiolitis adulthood asthma in the present study. Thus, depending on the
patients with less asthma later than in RSV-negative bronchi- individual baseline level of blood eosinophils, either low or
even normal eosinophils during viral infection may mean a
normal eosinopenic response to infection. In the present study,
Table 2 Early-life risk factors for asthma and irreversible bronchial the associations between eosinophil levels in infancy and
obstruction at the age of 28–31 years after bronchiolitis in infancy in asthma or lung function deficiency in adulthood were inde-
multivariate logistic regression model pendent from atopy in infancy, in line with previous findings
made in the American birth cohort study (15).
Self-reported FEV1/FVC <5th
Our finding that repeated wheezing at the age of 1–2 years
asthma* (N = 17) percentile† (N = 7)
Risk or protective and repeated wheezing at under 2 years of age are significant
factors OR‡ 95% CI§ OR‡ 95% CI§ risk factors for asthma in adulthood is in line with other studies
(3, 4). The start of wheezing symptoms during the second or
Female gender 1.56 0.36–6.77 1.52 0.20–11.79 third years of life is a more important risk factor for later
(N = 18) asthma than the start during the first year of life (25–27). All
Current smoking 0.53 0.09–3.07 0.44 0.05–3.52 children who had history of parental asthma had repeated
(N = 14) wheezing under 2 years of age, and due to this strong
Atopy¶ (N = 24) 0.91 0.19–4.29 0.16 0.01–1.96
interaction, repeated wheezing in early childhood was not
Parental asthma** 0.96 0.16–5.69 16.52 1.09–249.88
any more a significant risk factor in multivariable analyses. In
(N = 7)
previous studies, family history of asthma has increased the
Repeated wheezing 5.48 0.81–37.09 0.75 0.08–7.41
risk of asthma and lung function abnormalities up to the early
at <2 years††
adulthood (1, 6). In the present study, family history of asthma
(N = 31)
was not a significant risk factor for asthma, but was for lung
*For definition of asthma, please see the text. function impairment in adulthood, suggesting a significant role
†FEV1/FVC ratio below 5th percentile lower limit of normality after for heredity also in lung function.
bronchodilatation test. In the earlier phases of this follow-up study, non-RSV
‡Odds ratio, logistic regression: all variables in the table included in etiology of bronchiolitis was a consistent risk factor for asthma
the model. until the age of 18–20 years (7). Now, this association could not
§95% confidence interval. be detected. Most non-RSV cases were negative also in the tests
¶Doctor-diagnosed atopic dermatitis and/or high serum IgE >60 IU//l for adenoviruses; parainfluenza 1, 2, and 3 viruses; and influenza
at the age of <2 years. A and B viruses (11). Probably, a substantial number of non-
**Doctor-diagnosed parental asthma present. RSV cases were caused by rhinoviruses, which is currently
††More than two doctor-diagnosed wheezing episodes during the
known to be the most important asthma-predictive virus in
follow-up period.
young wheezing children (28). In 1980 when the study started,

Table 3 Blood eosinophils on admission and on convalescence 4–6 weeks after bronchiolitis in relation to self-reported asthma and irreversible
airways obstruction in adulthood in adjusted logistic regression model

Self-reported asthma* FEV1/FVC<5th percentile†

(N = 17) (N = 7)

Risk or protective factor OR‡ 95% CI§ OR‡ 95% CI§

Blood eosinophils <0.25 9 10/E9/l on admission¶ (N = 11) 0.17 0.04–0.68 0.18 0.03–1.20
Blood eosinophils >0.45 9 109/l on admission¶ (N = 11) 2.00 0.44–9.14 8.35 1.15–60.64
Blood eosinophils <0.25 9 109/l on convalescence** (N = 25) 0.40 0.11–1.47 1.22 0.21–6.98
Blood eosinophils >0.45 9 10/E9/l on convalescence** (N = 9) 6.30 1.13–35.30 2.69 0.33–21.78

*For definition of asthma, please see the text.

†FEV1/FVC ratio below 5th percentile lower limit of normality after bronchodilatation test.
‡Odds ratio, logistic regression: adjusted with gender, current smoking, and atopy (atopic dermatitis and/or high serum IgE >60 IU/l) in infancy.
§95% confidence interval.
¶On admission to hospital for bronchiolitis.
**On convalescence, 4–6 weeks after bronchiolitis.

Pediatric Allergy and Immunology 26 (2015) 668–673 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 671
Blood eosinophils and asthma Backman et al.

advanced virus antigen direct detection technology was in use
for RSV and some other viruses, but polymerase chain reaction
technology for rhinoviruses has been developed much later.
Subepithelial fibrosis in the airways, characteristic for
allergic asthma, is mediated by an eosinophilic inflammation
(29). Eosinophils contain several cytotoxic substances, such as
eosinophil cationic protein, which can promote inflammation
and tissue damage in the lungs (29). The present study revealed
that eosinophilia during bronchiolitis predicted lung function
impairment continuing up to adulthood, possibly reflecting
eosinophil-mediated changes in the lung tissue.
In a recent Norwegian post-bronchiolitis study, higher blood
eosinophil counts during bronchiolitis during the first year of
life were documented in children with asthma at 11 years of
age than in those without asthma (30). In addition, blood
eosinophils during infant bronchiolitis were positively associ-
ated with bronchial hyper-reactivity and negatively associated
with FEV1 in FVS (30). The age definition of bronchiolitis –
less than 12 months – is in line with the current European
practice, whereas our patients represent a more heterogeneous
group of less than 24-month-old wheezers. However, the
authors did not present any analyses with eosinophils catego-
rized as low (eosinopenia) or high (eosinophilia), and therefore,
exact comparisons with our result are not possible.
The main strength of the study is the long prospective
follow-up of 30 years after hospitalization for bronchiolitis.
The data including laboratory studies such as eosinophil
counting on admission to hospital in infancy and on conva-
lescence during control visits were carefully collected. The main
shortcoming of the study is the small number of subjects.
Although current asthma (36%) and irreversible airway
obstruction (15%) were rather common, the power of the
study was not enough to find all early-life risk or protective
factors, as can be seen in some very large confidence intervals.
Many early-life risk factors that were previously associated
with increased risk for asthma had lost their significance at the
age of 28–31 years, but due to low power of the study, their
impact cannot be ruled out. On the other hand, the robustness
of the findings of low eosinophils as a protective factor for
asthma and eosinophilia as a risk factor for asthma and airway
impairment highlights the importance of these observations.
In conclusion, eosinophil inflammation during infant bron-
chiolitis may have a long-term impact on lung function and
airway responsiveness. Eosinopenia during infant bronchiolitis
predicted low asthma risk, and eosinophilia after bronchiolitis
predicted high asthma risk up to the age of 28–31 years.
Eosinophilia during bronchiolitis was a risk factor for irre-
versible airway obstruction.

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