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\begin{document}

\title{Serum periostin levels are associated with asthma severity in children}



\author[1]{S. Tolga Yavuz}%
\author[1]{Soyhan Bagci}%
\author[2]{Ahmet Bolat}%
\author[2]{onur akın}%
\author[1]{Rainer Ganschow}%
\affil[1]{Children's Hospital, University of Bonn}%
\affil[2]{Gülhane Training and Research Hospital}%


\vspace{-1em}



  
  \date{May 05, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Periostin has emerged as a novel biomarker in the
pathogenesis of T helper 2-type allergic diseases in the last years. The
aim of this study was to investigate the association of serum periostin
levels with clinical features in children with asthma. Methods: Children
with physician-diagnosed asthma who attended regularly to an outpatient
pediatric allergy and asthma center were enrolled in the study along
with control subjects. Asthma severity and control status of the
patients were evaluated according to recent GINA guidelines. Results: A
total of 158 children (125 with asthma and 33 age and sex-matched
control subjects) with a median age of 10.2 years (range 5.9-17.0) were
enrolled. Asthma severity was mild in 41 (32.8\%), moderate in 63
(50.4\%) and severe in 21 (16.8\%) children. Children with asthma had
significantly higher periostin levels than controls (53.1 \selectlanguage{ngerman}± 13.1 vs 43.0
± 11.2 ng/mL; p \textless{} 0.001). The mean serum periostin levels of
children with severe asthma (63.8 ± 10.8) were significantly higher than
in children with moderate asthma (53.3 ± 12.7) and mild asthma (47.4 ±
11.1) (p \textless{} 0.001). Serum periostin levels were found to be
significantly correlated with asthma severity (Spearman's rho
{[}r{]}=0.41, p \textless{} 0.001). Results of multivariable logistic
regression analysis demonstrated an association between serum periostin
levels and asthma severity in children (OR, 1.10; 95\% CI, 1.04-1.15; p
\textless{}0.001) Conclusion: Serum periostin levels may serve
clinicians in identifying children with severe asthma.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\emph{Disclosure of potential conflict of interest:} The authors declare
that they have no conflict of interests.

\emph{The authors received no financial support for the research,
authorship, and/or publication of this article.}

\textbf{ABSTRACT}

\textbf{Background:} Periostin has emerged as a novel biomarker in the
pathogenesis of T helper 2-type allergic diseases in the last years. The
aim of this study was to investigate the association of serum periostin
levels with clinical features in children with asthma.

\textbf{Methods:} Children with physician-diagnosed asthma who attended
regularly to an outpatient pediatric allergy and asthma center were
enrolled in the study along with control subjects. Asthma severity and
control status of the patients were evaluated according to recent GINA
guidelines.

\textbf{Results:} A total of 158 children (125 with asthma and 33 age
and sex-matched control subjects) with a median age of 10.2 years (range
5.9-17.0) were enrolled. Asthma severity was mild in 41 (32.8\%),
moderate in 63 (50.4\%) and severe in 21 (16.8\%) children. Children
with asthma had significantly higher periostin levels than controls
(53.1 \selectlanguage{ngerman}± 13.1 vs 43.0 ± 11.2 ng/mL; p \textless{} 0.001). The mean serum
periostin levels of children with severe asthma (63.8 ± 10.8) were
significantly higher than in children with moderate asthma (53.3 ± 12.7)
and mild asthma (47.4 ± 11.1) (p \textless{} 0.001). Serum periostin
levels were found to be significantly correlated with asthma severity
(Spearman's rho {[}r{]}=0.41, p \textless{} 0.001). Results of
multivariable logistic regression analysis demonstrated an association
between serum periostin levels and asthma severity in children (OR,
1.10; 95\% CI, 1.04-1.15; p \textless{}0.001)

\textbf{Conclusion:} Serum periostin levels may serve clinicians in
identifying children with severe asthma.

\textbf{Keywords:} asthma, biomarker, children, periostin, severe
asthma.

\textbf{Key messages:} Periostin, which has emerged as a novel biomarker
in the pathogenesis of T helper 2-type allergic diseases in the last
years, may serve clinicians in the diagnosis and follow-up of children
with severe asthma.

\textbf{Serum periostin levels are associated with asthma severity in
children}

\textbf{INTRODUCTION}

Asthma is one of the most common chronic diseases of childhood and
type-2 airway inflammation is the major feature of the disease. The
emergence of biomarkers associated with the underlying airway
inflammation is an active research area in adults and children. Up to
date, only a limited number of biomarkers have been routinely used in
daily clinical practice in patients with asthma and there is still a
need for a reliable biomarker not only for the prediction, diagnosis or
follow-up of asthma, but also as a candidate target for the treatment
options in the future (1).

Periostin is an extracellular matrix protein expressed in fibroblasts
and airway epithelial cells and has emerged as a novel biomarker in the
pathogenesis of T helper 2-type allergic diseases in the last years. Its
role in the diagnosis and treatment of asthma has been highlighted in
several adult studies. However, there are limited studies with
inconclusive data about the clinical utility of periostin in children
with asthma (2).

The aim of this study was to investigate the association of serum
periostin levels with several clinical features in children with asthma.



\textbf{METHODS}

\textbf{Study design, setting and participants}

Children aged 6 to 17 with physician-diagnosed asthma who were regularly
followed up in the Pediatric Allergy and Asthma Unit of Gulhane School
of Medicine between 2014 and 2017 were enrolled in the study along with
age and sex-matched control subjects without any physician diagnosed
asthma who admitted to outpatient department of our unit for routine
medical checkup. They had no history of wheezing or infection during the
last 4 weeks before the study enrollment.

Asthma was defined as current symptoms (wheeze and cough) and positive
bronchodilator responsiveness (improvement of FEV\textsubscript{1} by
12\% or more following administration of 200 mcg salbutamol), and/or a
positive response to a trial of therapy with inhaled or oral
corticosteroids (3). Asthma severity is assessed retrospectively from
the level of treatment required to control symptoms and exacerbations in
the last year according to GINA guidelines. ``Mild asthma'' is asthma
that is well controlled with Step 1 or Step 2 treatment, ``moderate
asthma'' is asthma that is well controlled with Step 3 treatment and
``severe asthma'' is asthma that requires Step 4 or 5 treatment. Asthma
control status of the patients were also evaluated according to GINA
guidelines (3). Patients with an acute exacerbation of asthma requiring
systemic corticosteroids during the previous 3 months and other known
systemic disorders were excluded.

The study was approved by the institutional review board of Gulhane
School of Medicine and written informed consent was obtained from
parents.

Study measurements

\emph{Skin tests}

All children underwent skin prick testing (SPT) to common aeroallergens
for our region (4), including house-dust mites (\emph{Dermatophagoides
pteronyssinus} and \emph{Dermatophagoides farinae} ), grass pollen mix
(Phleum pratense, Poa pratensis, Dactylis glomerata, Lolium perenne,
Festuca pratensis, and Avena eliator) weed pollen mix (Artemisia,
Urtica, Taraxacum, Plantago) tree pollen mix (Alnus glutinosa, Corylus
avellane, Populus alba, Ulmus minor, Betula alba) molds (Alternaria,
Cladosporium, Penicillium, and Aspergillus) and animal dander (cat and
dog). Histamine (10 mg/ml of histamine phosphate) and 0.9\% saline were
used as positive and negative controls, respectively. Weal 3 mm greater
than negative control was considered a positive reaction.

\emph{Anthropometric measures}

Children were weighed wearing minimal clothes and without shoes, Height
was rounded to the nearest 0.1 cm and weight was rounded to the nearest
0.1 kg. Subsequently, BMI (Body mass index) was calculated as weight
(kilograms) divided by height (meters) squared. BMI z-scores of
participants were also calculated (5).

\emph{Blood eosinophil counts and serum total IgE levels}

Blood eosinophil counts were determined from Coulter Counter (Beckman
Coulter, Fullerton, CA, USA) leucocyte measurements. Total serum IgE
level was measured using ImmunoCAP (Phadia AB, Uppsala, Sweden).

\emph{Serum periostin levels}

Measurement of serum periostin levels were made with an enzyme-linked
immunosorbent assay (ELISA) at Shino-Test (Kanagawa, Japan), as
described previously (6).

\emph{Pulmonary function tests}

Pulmonary function tests were performed using Zan 100 spirometer (Nspire
Health, Oberthulba, Germany) according to recommendations by the
European Respiratory Society (7). FEV\textsubscript{1},
FEV\textsubscript{1}/FVC, and FEF\textsubscript{25-75} were recorded
(8).

\textbf{Statistical Analysis}

Analyses were performed using SPSS Statistics v21.0 (IBM, Chicago, IL,
USA). Normally-distributed continuous data were expressed as mean and
standard deviation, and not-normally distributed continuous data as
median and interquartile ranges (IQR). Group comparisons were carried
out using student´s t-test, Mann--Whitney U-test or ANOVA as appropriate
for the continuous, and the chi-square test or Fisher test for
categorical variables. The correlation coefficients between serum
periostin level and other clinical variables were determined using
Spearman`s rank correlation coefficient. Association of severe asthma
classes with clinical variables was examined using regression models
adjusted for potential confounders, including age, aeroallergen
sensitization, BMI z-score, blood eosinophil count and serum periostin
level. The odds ratio (OR) and 95\% confidence interval (CI) were
reported. The diagnostic performances of serum periostin levels to
identify children with severe asthma were determined by receiver
operating characteristic (ROC) curve analysis. Sensitivity, specificity,
positive predictive value (PPV), and negative predictive value (NPV)
were calculated for the selected cut-off point. A \emph{P} level
\textless{}0.05 was considered significant.

\textbf{RESULTS}

\emph{Descriptive statistics}

A total of 158 children (125 with asthma and 33 age and sex-matched
control subjects) with a median age of 10.2 years (range 6.0-17.0) were
enrolled. Characteristics of the study groups are presented in Table 1.
There were no significant differences between the children with asthma
and control groups in terms of age, sex, body mass index and total IgE
levels. The prevalence of aeroallergen sensitization was significantly
higher in children with asthma and they had significantly higher blood
eosinophil counts. Children with asthma had significantly higher
periostin levels than controls (53.1 ± 13.1 vs 43.0 ± 11.2 ng/mL; p
\textless{} 0.001) (Figure 1a).

\emph{Clinical features of children with asthma}

Clinical characteristics of the children with asthma are presented in
Table 2. Of these 125 children with asthma, 41 (32.8\%) had mild, 63
(50.4\%) had moderate and 21 (16.8\%) had severe asthma. Asthma was
controlled in 58.4\% of the patients. 69 children (55.2\%) were under
regular asthma controller treatment and 52 children (41.8\%) had an
asthma exacerbation in the last year. 87 children (69.6\%) had an
aeroallergen sensitization.

\emph{Correlation between serum periostin levels and clinical variables
related to asthma}

Serum periostin levels were found to be significantly correlated with
asthma severity (Spearman's rho {[}r{]}=0.41, p \textless{} 0.001) and
BMI z score (r= -0.31, p \textless{} 0.001), whereas no correlations
were found with age, disease duration, accompanying atopic diseases such
as allergic rhinitis and atopic dermatitis, asthma control status, total
IgE levels, blood eosinophil counts and lung function parameters (Table
3).

\emph{Serum periostin levels and asthma}

The mean serum periostin levels of children with severe asthma (63.8 ±
10.8) were significantly higher than in children with moderate asthma
(53.3 ± 12.7) and mild asthma (47.4 ± 11.1) (p \textless{} 0.001)
(Figure 1b). No significant differences in serum periostin levels were
found in children with asthma when compared according to gender, asthma
control status, aeroallergen sensitization, presences of allergic
rhinitis or atopic dermatitis (Table 4).

\emph{Multivariable regression and ROC analyses for severe asthma}

Results of multivariable logistic regression analysis revealed that
serum periostin levels were associated with severe asthma in children
(OR, 1.10; 95\% CI, 1.04-1.15; P \textless{}0.001) (Table 5).

Analysis using ROC curves identified the role of serum periostin levels
in determining children with severe asthma (AUC: 0.77, 95\% CI:
0.67--0.87, P \textless{} 0.001{]}. When analysed for the best cut-off
value with the highest combined sensitivity and specificity, a cut-off
value of 52 ng/ml for serum periostin level was obtained with
sensitivity, specificity, PPV, and NPV of 100\%, 50\%, 29\%, and 100\%,
respectively.



\textbf{DISCUSSION}

In this cross-sectional study, we found that serum periostin levels were
significantly higher in children with asthma when compared to healthy
controls. Our results also found out an association between serum
periostin levels and asthma severity independent from the confounding
factors such as BMI and accompanying allergic diseases.

\emph{Periostin levels and asthma}

Results of several previous childhood studies have demonstrated an
association between serum periostin levels and asthma. Song et al. (9)
have found that serum periostin levels were higher in children with
asthma and associated with airway hyperreactivity. Inoue et al (10).
have also found significantly higher serum periostin levels in children
with asthma compared to children without any allergic disease in their
cross-sectional study and they indicated the possible role of serum
periostin in the diagnosis of childhood asthma. On the other hand, Inoue
et al. (11) did not detect any increase in serum periostin levels in
school age children with allergic diseases including asthma in
comparison to healthy children. The serum periostin levels were found to
be significantly higher in children than those in healthy adults. They
have speculated that the high baseline levels of serum periostin due to
increased bone metabolism in childhood might have masked the possible
further increase due to allergic diseases. In our study serum periostin
levels were higher in children particularly with moderate and severe
asthma.

\emph{Predictive role of periostin for asthma}

Several attempts were made to investigate the role of periostin to
predict the development of asthma in the future. Anderson at al.(12)
have prospectively followed up the children from COAST (Childhood
Origins of ASThma Study) cohort and longitudinally investigated the role
of several biomarkers of type 2 inflammation such as aeroallergen
sensitization, blood eosinophils and serum periostin levels in the
development of asthma during the childhood period. They have found that,
along with other variables, high serum periostin levels at the age of 2
years is a risk factor for asthma by school-age. However, they have also
addressed a concern regarding the possible confounder effect of the
linear growth on serum periostin levels during the early-childhood
phase. Castro-Rodriguez et al.(13) have performed a case-control study
in preschoolers with recurrent wheezing episodes and compared periostin
levels according to their asthma predictive index result. No significant
difference was found in periostin levels between children with positive
and negative asthma predictive index. Recently, Guvenir et al.(14)
investigated the role of periostin in young children with wheezing
episodes for the prediction of asthma development. However, their
results did not reveal periostin as a predictive factor for future
asthma in young children, either.

\emph{Association between asthma control and periostin}

There are conflicting results about the relationship between serum
periostin levels and asthma control status in children. El Basha et
al.(15) have found significantly higher serum periostin levels in
children during an asthma exacerbation compared to children with stable
asthma and healthy controls whereas In contrast to these findings Mena
et al. (16) have found an inverse association with lower serum periostin
levels in children with uncontrolled asthma. Licari et al. (17) did not
find an association between asthma control and serum periostin levels in
121 children with allergic asthma. In our study serum periostin was not
associated with asthma control, either. Asthma control status is
determined according to the symptoms in the last 4 weeks and it can be
different in every clinical visit. However, asthma severity is based on
the step of medications to control asthma symptoms in the last year and
it can be a better instrument in search of a biomarker that reflects the
degree of inflammation in a chronic disease like asthma.

\emph{Association between asthma severity and periostin}

There are also inconsistent results from the studies which investigated
the association between asthma severity and serum periostin levels. The
results of Licari et al.(17) and Konradsen et al. (18) did not reveal an
association between asthma severity and serum periostin levels. On the
other hand, Song et al. (9) have explored the relationship between
periostin and airway hyperresponsiveness (AHR) in children with asthma
and found a significant correlation between the degree of AHR and
periostin levels. Similarly, Cho et al. (19) found significantly higher
periostin levels in children with positive exercise and mannitol tests
when compared to children with asthma and negative results. Recently,
the findings of Knihtilä et al.(20) have demonstrated a significant
correlation between serum periostin levels, airway-hyperreactivity and
bronchodilator responsiveness in 49 children with asthmatic symptoms. In
our study we found a significant and independent correlation between
asthma severity and serum periostin levels. A serum periostin value of
52 ng/ml was emerged as the best cut-off level to differentiate children
with severe asthma with high sensitivity and negative predictive values,
whereas the specificity and positive predictive value for this cut-off
were not satisfactory. According to our findings, it can be postulated
that low serum periostin levels may serve clinicians better in excluding
severe asthma in children.

\emph{Body mass index and serum periostin}

In according with the previous adulthood studies (21, 22), we found a
negative correlation between serum periostin levels and body mass index
in children with asthma along with healthy controls. In our previous
studies, we have demonstrated associations between anthropometric
measures and asthma severity along with pulmonary functions (23-25). In
the current study, our results did not reveal an independent association
between body mass index and asthma severity. The different study design
and the lack of controls group with obese children is the most plausible
explanation. Addition of serum periostin measurement into the studies
can help us to better understand the interaction between obesity and
asthma in the future.

\emph{Limitations and strengths}

There are several limitations in the present study. First, the
diagnostic performance of serum periostin in identifying children with
severe asthma were relatively low. It seems that further studies
including more children particularly with severe asthma can help to
determine different cut-off values with better statistical performances.
Furthermore, periostin is a bone-derived extracellular matrix protein
that is secreted by osteoblasts and in growing children the indicative
role of periostin related to the airway inflammation and consequently
asthma severity may be affected due to the fast-linear growth in
school-age children. On the other hand, it was performed in a center
which was specialized for children with asthma and allergic diseases.
The diagnostic procedures and the longitudinal follow-up of the patients
were made by pediatric allergy and asthma specialists conforming with
the international standard GINA guidelines. Its controlled design with
the inclusion of patients with different severity grades who were under
regular follow-up enabled us to demonstrate the possible interactions
between features related to childhood asthma and periostin.

\emph{Conclusion}

In conclusion, we demonstrated a significant and independent association
between serum periostin and asthma severity in children. Our findings
highlight the diagnostic role of periostin in identifying children with
severe asthma. Further studies are needed to better demonstrate the role
of periostin in the asthma pathogenesis and clinical utility for the
physicians dealing with children with asthma.

\textbf{Acknowledgements:} We are extremely grateful to all the patients
and their families who took part in this study. We would also like to
acknowledge the hard work and dedication of the study team, which
includes physicians, laboratory technicians and nurses.



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\textbf{Table 1.} Demographic and laboratory characteristics of the
study groups (n=158)\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asthma (n=125)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Control (n=33)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
p-value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (years)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10.2 (7.8-12.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11.4 (7.5-13.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.53\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Male sex, (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
75.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
66.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.32\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19.8 \selectlanguage{ngerman}± 4.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19.4 \selectlanguage{ngerman}± 4.1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.72\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI z-score\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.45 \selectlanguage{ngerman}± 1.25\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.44 \selectlanguage{ngerman}± 1.08\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aeroallergen sensitization, (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
69.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Serum periostin (ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
53.1 \selectlanguage{ngerman}± 13.0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
43.3 \selectlanguage{ngerman}± 11.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eosinophils, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.4 (2.1-5.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.1 (1.4-3.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.007\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eosinophils, (/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
255 (150-428)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
120 (80-230)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Total IgE (IU/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
71 (20-167)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (11-138)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.12\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: BMI, body mass index. Data are presented as percentage,
median (interquartile range) or mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: BMI, body mass index. Data are presented as percentage,
median (interquartile range) or mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: BMI, body mass index. Data are presented as percentage,
median (interquartile range) or mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: BMI, body mass index. Data are presented as percentage,
median (interquartile range) or mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 2.} Clinical characteristics of the children with asthma
(n=125)\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Age at symptoms start (years) & 4.5 (2.0-7.0)\tabularnewline
Age at the diagnosis (years) & 6.3 (4.8-9.8)\tabularnewline
Disease duration (years) & 5.1 (2.4-7.9)\tabularnewline
Allergic rhinitis & 61.6\tabularnewline
Atopic dermatitis & 13.6\tabularnewline
Asthma controller therapy & 55.2\tabularnewline
Asthma exacerbation in last year & 41.6\tabularnewline
Asthma severity - mild - moderate - severe & 32.8 50.4
16.8\tabularnewline
Asthma control level - controlled - partially controlled - uncontrolled
& 58.4 20.8 20.8\tabularnewline
Aeroallergen sensitization &\tabularnewline
- Grass pollens & 57.6\tabularnewline
- House dust mites & 18.4\tabularnewline
- Cat dander & 11.2\tabularnewline
- Mold & 8.0\tabularnewline
- Dog dander & 6.4\tabularnewline
- Tree pollens & 4.0\tabularnewline
- Weed pollens & 3.2\tabularnewline
Data are presented as percentage or median (interquartile range) & Data
are presented as percentage or median (interquartile
range)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3.} Spearman's correlation coefficients between serum
periostin level and other clinical variables in children with asthma\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& & Serum periostin (ng/ml) & Serum periostin (ng/ml)\tabularnewline
& & r & p-value\tabularnewline
Age, years & Age, years & -0.15 & 0.11\tabularnewline
Disease duration, years & Disease duration, years & -0.06 &
0.56\tabularnewline
Asthma severity & Asthma severity & 0.41 & \textless{}
0.001\tabularnewline
Asthma control status & Asthma control status & -0.01 &
0.92\tabularnewline
Atopic dermatitis & Atopic dermatitis & 0.11 & 0.23\tabularnewline
Allergic rhinitis & Allergic rhinitis & 0.04 & 0.70\tabularnewline
BMI, z-score & BMI, z-score & -0.31 & \textless{} 0.001\tabularnewline
Total IgE (IU/mL) & Total IgE (IU/mL) & 0.03 & 0.78\tabularnewline
Eosinophils, (\%) & Eosinophils, (\%) & -0.18 & 0.06\tabularnewline
Eosinophils, (/ml) & Eosinophils, (/ml) & -0.18 & 0.05\tabularnewline
FEV\textsubscript{1,} pred \% & FEV\textsubscript{1,} pred \% & 0.04 &
0.66\tabularnewline
FEV\textsubscript{1}/FVC ratio & FEV\textsubscript{1}/FVC ratio & 0.10 &
0.26\tabularnewline
FEF\textsubscript{25-75}, pred \% & FEF\textsubscript{25-75}, pred \% &
0.04 & 0.69\tabularnewline
Abbreviations: BMI, body mass index; FEF\textsubscript{25-75}, forced
expiratory flow between 25\% and 75\%; FEV\textsubscript{1}, forced
expiratory volume during first second; FVC, forced vital capacity &
Abbreviations: BMI, body mass index; FEF\textsubscript{25-75}, forced
expiratory flow between 25\% and 75\%; FEV\textsubscript{1}, forced
expiratory volume during first second; FVC, forced vital capacity &
Abbreviations: BMI, body mass index; FEF\textsubscript{25-75}, forced
expiratory flow between 25\% and 75\%; FEV\textsubscript{1}, forced
expiratory volume during first second; FVC, forced vital capacity &
Abbreviations: BMI, body mass index; FEF\textsubscript{25-75}, forced
expiratory flow between 25\% and 75\%; FEV\textsubscript{1}, forced
expiratory volume during first second; FVC, forced vital
capacity\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4.} Comparison of serum periostin levels according to
clinical variables in children with asthma\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Serum periostin (ng/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
p-value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Gender -boys -girls\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
53.8 \selectlanguage{ngerman}± 13.5 51.3 ± 11.6\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.36\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Asthma severity -mild -moderate -severe\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
47.4 \selectlanguage{ngerman}± 11.1 53.3 ± 12.7 63.8 ± 10.8\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textless{}.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Asthma control status -controlled -partially controlled
-uncontrolled\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
52.9 \selectlanguage{ngerman}± 13.4 56.7 ± 12.1 50.1 ± 12.4\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.18\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Aeroallergen sensitization -yes -no\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
54.3 \selectlanguage{ngerman}± 12.9 50.4 ± 12.9\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.13\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Atopic dermatitis -yes -no\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
55.7 \selectlanguage{ngerman}± 12.5 52.7 ± 13.1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.38\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Allergic rhinitis -yes -no\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
53.6 \selectlanguage{ngerman}± 12.4 52.4 ± 14.1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Data are presented as mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Data are presented as mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Data are presented as mean \selectlanguage{ngerman}± standard deviation\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 5.} Multivariable logistic regression analysis for severe
asthma\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Variable & OR (95\% CI) & p-value\tabularnewline
Age & 1.11 (0.91-1.34) & 0.31\tabularnewline
Aeroallergen sensitization & 0.44 (0.15-1.32) & 0.14\tabularnewline
BMI, z-score & 1.01 (0.65-1.58) & 0.96\tabularnewline
Eosinophils (/ml) & 1.01 (0.99-1.01) & 0.23\tabularnewline
Serum periostin level & 1.10 (1.04-1.15) &
\textless{}0.001\tabularnewline
Abbreviations: BMI: Body mass index; CI, confidence interval; OR, odds
ratio & Abbreviations: BMI: Body mass index; CI, confidence interval;
OR, odds ratio & Abbreviations: BMI: Body mass index; CI, confidence
interval; OR, odds ratio\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure Legends}

\textbf{Figure 1.} Comparison of serum periostin levels in study groups

1a. Asthma vs Healthy controls

1b. Asthma group according to severity

\textbf{Hosted file}

\verb`Figure 1.pptx`  available at \url{https://authorea.com/users/381831/articles/497732-serum-periostin-levels-are-associated-with-asthma-severity-in-children}

\selectlanguage{english}
\FloatBarrier
\end{document}

