Respiratory Medicine 145 (2018) 8–13

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Asthma control in preschool children with small airway function as T

measured by IOS and fractional exhaled nitric oxide
Jing Zeng1, Zhiqiang Chen1, Ying Hu, Qi Hu, Shimin Zhong, Wei Liao∗
Department of Pediatrics, First Affiliated Hospital to Army Medical University, NO.30, Gao Tanyan Street, Shapingba District, Chongqing, China

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: This study investigated the accuracy of impulse oscillometry (IOS) combined with fractional exhaled
Asthma nitric oxide (FeNO) to assess asthma control among preschool children.
Exhaled nitric oxide Methods: A total of 79 preschool children(3–6 year old) with asthma and 25 healthy preschool children who
Asthma control visited a paediatrician were enrolled in this study. All of the children were tested for allergens, respiratory
Children
system resistance (at 5 and 20 Hz [R5, R20]), respiratory system reactance (at 5 Hz [X5]), the resonant frequency
Small airway function
of reactance (Fres), and the area under the reactance curve (between 5 Hz and Fres (reactance area [AX]) using
IOS and FeNO. A paediatric respiratory specialist who was unaware of the IOS and FeNO results assigned
children with asthma to either the asthma-controlled group (n = 27) or the asthma-uncontrolled group (n = 52)
based on the Global Initiative for Asthma (GINA) criteria. A healthy control group (n = 25) was also included.
The relationships between the FeNO and IOS values as well as the asthma control of the three groups were
analysed, and the areas under the curve (AUCs) were calculated for each measure.
Results: (1) During the controlled group, means ± standard deviations of AX, R5-20, R5, X5 and FeNO were
26.15 ± 7.534, 3.52 ± 1.311,9.97 ± 1.576,-3.85 ± 0.572,-3.85 ± 0.572. During the uncontrolled group,
means ± standard deviations of AX,R5-20,R5,X5 and FeNO were
38.34 ± 13.563,5.36 ± 1.545,11.41 ± 2.029,-5.07 ± 1.554,36.40 ± 21.07. Among preschool children,
significant differences were observed between the controlled and uncontrolled group with regard to the small
airway functional parameters (AX, R5-20, R5, and X5) and FeNO(P < 0.05).(2) A receiver operating char-
acteristic (ROC) analysis showed that the AUCs were 0.786 for FeNO alone, 0.751 for X5 alone, and 0.866 for X5
combined with FeNO (cut-off value: 27 ppb).
Conclusion: FeNO combined with the small airway function parameter X5 accurately assessed asthma control
among preschool children.

Childhood asthma usually occurs before age 3. Pulmonary impair-
ment often starts during the preschool ages among children with
asthma. Therefore, guidelines recommend that asthma treatment start
as early as possible to achieve full control [1]. Current guidelines re-
commend using the Test for Respiratory and Asthma Control in Kids
(TRACK) to assess the respiratory and asthma control of preschool
children with asthma [2]. This test has been used in Turkey and Spain
with satisfactory reliability and validity [3,4]; however, the Chinese
version of the TRACK has not been widely used in China, and research
is needed to confirm its effectiveness and reliability [5]. Moreover,
clinicians need an objective, accurate, and non-invasive method to as-
sess asthma control among preschool children.
Asthma is an inflammatory disease characterised by small airway
obstruction. A growing body of evidence shows that small airway
function is closely related to asthma control, acute exacerbation, and
prognosis [6–8]. Currently, a forced expiratory flow (FEF) of 25–75%
(i.e., a mean flow between 25% and 75% of forced expiration) is the
most commonly used small airway functional parameter in clinical
practice. However, preschool children are too young to understand the
instructions associated with this test and cannot perform it; thus, the
use of this parameter is limited. The advent of impulse oscillometry
(IOS) technology solves this problem. During this test, the patient
breathes normally without the need to actively cooperate; as a result,
the test is suitable for children aged > 3. Moreover, studies have shown

∗
Corresponding author. Department of Pediatrics, First Affiliated Hospital to Army Medical University, NO.30, Gao Tanyan Street, Shapingba District, Chongqing,
400038, China.
E-mail addresses: zengjing8903@163.com (J. Zeng), chenzhiqiang_cc@163.com (Z. Chen), huyingxixi@sina.com (Y. Hu), 861097015@qq.com (Q. Hu),
26898649@qq.com (S. Zhong), liaowei01@163.com (W. Liao).
1
Common first author: The first author and the common first author have the same contribution to the article.

https://doi.org/10.1016/j.rmed.2018.10.009
Received 19 June 2018; Received in revised form 4 September 2018; Accepted 10 October 2018
Available online 16 October 2018
0954-6111/ © 2018 Elsevier Ltd. All rights reserved.
J. Zeng et al.
that among the IOS parameters, R5-20 (the difference between R5
[respiratory system resistance at 5] and R20[respiratory system re-
sistance at 20]), AX (reactance area), X5 (reactance of the respiratory
system at 5 Hz), and Fres (resonant frequency of reactance) are useful
with regard to small airway function [9,10].
In addition to IOS parameters, recent studies have shown that
fractional exhaled nitric oxide (FeNO) can be used to assess both central
and small airway function [11,12]. The American Thoracic Society
(ATS) recommends FeNO as a reactive airway inflammation biomarker,
especially for airway eosinophilic inflammation [13]. The FeNO test is
easy to perform, non-invasive, and reproducible; thus, it is particularly
suited for preschool children. The guidelines also mention that con-
tinuous FeNO monitoring helps to assess asthma control and guide
treatment planning [1]. In addition, Liu et al. showed that IOS com-
bined with FeNO was highly sensitive and specific when assessing small
airway function [14]. Previous studies have only used FeNO or IOS
parameters (R5-20, AX, Fres, and X5) to assess asthma control
[10,15,16]. To date, few studies have been conducted to investigate the
use of IOS combined with FeNO to assess asthma control, and most
previous work has focused on children aged 6 and above or adults. The
pulmonary lobules are not fully developed until 6 years old. Thus, the
anatomy and physiological function of the pulmonary lobules might
differ between preschool children and adults. This cross-sectional study
investigated the value and significance of IOS combined with FeNO to
assess asthma control among preschool children.
1. Materials and methods
1.1. Participants
Preschool children with asthma diagnosed by a paediatric re-
spiratory specialist (unaware of this study) at the Southwest Hospital of
the Third Military Medical University, China between April 2015 and
February 2017 according to the Guidelines for the Diagnosis and
Treatment of Childhood Bronchial Asthma (2008) [17] were enrolled in
this study. The patients were given low-dose inhaled corticosteroids
(ICSs) and followed up for 3 months. At the end of the follow-up period,
the respiratory specialist assessed asthma control according to the
above guidelines [17]. The patients were screened for eligibility ac-
cording to the inclusion and exclusion criteria. Eligible children with
asthma were divided into the controlled group and the uncontrolled
group (including partially controlled cases). Moreover, 25 healthy
children (same age and sex ratio) who visited the hospital during the
same study period for health check-up were included as the healthy
group.
This study was approved by the Ethics Committee of the First
Affiliated Hospital of the Third Military Medical University. The family
members of each patient signed an informed consent document prior to
inclusion.
1.11 Inclusion criteria: 1) boys and girls are 3–6 years old; 2) di-
agnosed with bronchial asthma in the past; 3) mild-to-moderate
asthma, with the regular use of low-dose ICSs for 3 months; 4) receiving
IOS and FeNO tests after 3 months of treatment.
1.12 Exclusion criteria: 1) chronic active lung disease; 2) acute ex-
acerbation of asthma 4 weeks before study enrolment requiring sys-
temic corticosteroids; 3) the use of ICSs, short-acting bronchodilators,
or both 6 h before the IOS test; 4) strenuous exercise 4 h before the
FeNO test; and 5) the consumption of high-nitrogen foods such as spi-
nach and offal before the FeNO test or coffee, cola, or other stimulants
2 h before the FeNO test.
1.2. FeNO test
A nitric oxide analyser (Sunvou-P100; China) was used to measure
FeNO according to the FeNO standard test guidelines of the ATS/
European Respiratory Society (ERS) [18]. The test was repeated three
9
Respiratory Medicine 145 (2018) 8–13
times, and the mean value was used for subsequent analyses.
1.3. IOS
An IOS analyser (Jaeger, German) was used to measure R5, R20, R5-
20, AX, X5, and Fres according to the ERS standards [19], where R5 is
the total resistance of the small and large airways (total airway re-
sistance), R20 is the central airway resistance, R5-20 is the peripheral
airway resistance, AX is the reactance area, X5 is the reactance of the
respiratory system, and Fres is the resonant frequency of reactance. The
mean values were used for subsequent analyses.
1.4. Sample size and statistical analysis
1.4.1. Sample size
In this study, the AX values taken from Shi et al. [10] and Batmaz
et al. [20] were used to calculate sample size. The following equation
was used to calculate the sample size of this two-arm, parallel control,
superiority study that compared the means between two groups:
(Z1 − α + Z1 − β )2 × (σ12 + σ22)
N= Specifically, α = 0.05 (two-tailed),
(μ1 − μ2 − δ )2
β = 0.10, μ1 = 2.08, μ2 = 1.41, σ1 = 0.622, σ2 = 0.742, and δ = 0.67;
thus, 22 patients should be enrolled in each group. Taking into account
drop-outs and other interfering factors, 25 patients should be enrolled
in each group.
1.4.2. SPSS v19.0 was used for all statistical analyses
Sex was indicated as either M or F. A chi-square test was performed
for multi-group comparison. Measurement data were expressed as
means ± standard deviations (x¯ ± s ) . One-way analysis of variance
(ANOVA) were performed for multi-group comparisons. An F-test was
performed in cases of variance homogeneity, and Bonferroni tests were
performed for multiple comparisons. Welch's t-test was performed in
cases of variance heterogeneity, and Dunnett's T3 test was performed
for multiple comparisons. P < 0.05 was considered significant. In the
upper right corner of P value: "&" is the representative of F test; "&&" is
the representative of Bonferroni test; "#" is the representative of Welch
approximate F test; "##" is the representative of Dunnett's T3 test.
2. Results
2.1. Baseline clinical characteristics
We analysed the baseline data of children with asthma, including
their height, weight, and age. No significant differences were observed
regarding these data among the controlled group, the uncontrolled
group, and the healthy group (P > 0.05; Tables 1 and 2).
2.2. Significant differences in the FeNO and IOS parameters AX, R5-20,
and X5
Significant differences were observed in the FeNO and IOS para-
meters AX, R5-20, R5, and X5 between the controlled and uncontrolled
groups (Table 2). These parameters were significantly lower in the
former than in the latter (Fig. 1A, B, C, D, F). No significant difference
in R20 or Fres was observed among the three groups (Fig. 1E and G).
2.3. The high predictive value of FeNO combined with the IOS parameter X5
for asthma control
The receiver operating characteristic (ROC) analysis of asthma
control showed that area under the curve (AUC) was 0.786 for FeNO
alone, 0.751 for X5 alone, and 0.866 for X5 combined with FeNO
(27 ppb), suggesting that the bronchial hyperresponsiveness parameter
X5 is better than FeNO for assessing asthma control, and X5 combined
with FeNO is even better (Fig. 2, Tables 3 and 4).
J. Zeng et al. Respiratory Medicine 145 (2018) 8–13

Table 1
The baseline clinical characteristics of the controlled, uncontrolled, and healthy groups (x¯ ± s ) .
Demographic Parameters, Atopy, and Blood Eosinophil Counts of study subjects.
Healthy (N = 25) Asthma Status P

Controlled(N = 27) Uncontrolled(N = 52)

Sex(male/female) 17/8 19/8 28/24 0.26

Age(years) 3.92 ± 0.81 3.67 ± 0.62 3.63 ± 0.65 0.22&
Height(cm) 104.02 ± 5.48 104.12 ± 5.03 104.5 ± 6.70 0.93&
Weight(Kg) 21.3 ± 15.63 17.57 ± 2.55 17.64 ± 2.75 0.13#
BMI 19.09 ± 11.52 16.31 ± 1.34 16.21 ± 1.27 0.10#
Atopy(yes/no) 16/9 17/10 22/28 0.14
EOS( × 109/L) 0.37 ± 0.12 0.43 ± 0.27 0.38 ± 0.20 0.64#

Atopy: Atopy was defined as a skin test reaction to more than 1 of the 22 common aeroallergens and food allergens.
In the upper right corner of P value: "&" is the representative of F test; "#" is the representative of Welch approximate F test.

3. Discussion assessments include non-invasive pulmonary function tests and FeNO

Studies have shown that the incidence of childhood asthma has
increased by more than 50% per decade in China, and this condition is
higher in children younger than 6 years old. Currently, the asthma
control rate among children is lower in China than other countries.
Asthma control among children is closely related to asthma control,
lung function, and chronic obstructive pulmonary disease (COPD) in
adults [21,22]. Therefore, early asthma control and its assessment
during children is an important part of Standardized asthma manage-
ment. This study investigated that FeNO combined with the small
airway function parameter X5 accurately assessed asthma control
among preschool children.
Recently, small airway function assessment has attracted a great
deal of attention in the field of asthma assessment. the small airways
are defined as those without cartilage and a diameter of < 2 mm. They
contribute to only 10%–20% of the total airway resistance in healthy
adults; for infants and young children, however, the small airways
contribute to 50%–90% of the total airway resistance and play a key
role in asthma-related airway obstruction. Therefore, it is important to
assess small airway function in preschool-age children with asthma. At
present, the Th2 cytokines produced by the small airways, including the
alveoli, are likely the leading cause of reversible airway obstruction.
Thus, small airway dysfunction must be managed during asthma
treatment [23]. Usmani et al. concluded that asthma control is closely
related to improvements in small airway function [7]. A systematic
review showed that small airway dysfunction is present even in patients
with mild asthma, and small airway function is closely related to
asthma control, acute exacerbation, and the clinical characteristics of
asthma [8].
At present, small airway function assessments include functional
tests (e.g., pulmonary function), biological tests (e.g., FeNO), imaging
studies (e.g., high-resolution computed tomography [CT]), and invasive
tests (e.g., fibreoptic bronchoscopy). Among children, the best
measurement. FEF 25–75 (i.e., a mean flow between 25% and 75% of
forced expiration) is a commonly used small airway functional para-
meter in clinical practice. However, preschool children are unable to
cooperate during the test, which has limited the use of this parameter.
IOS testing does not require active cooperation and can be performed
under normal breathing, making it especially suitable for children
younger than 6 years old who are unable to complete conventional
pulmonary function tests. IOS parameters at different frequencies re-
flect the resistance of different parts of the respiratory system, whereas
R5-20, X5, and AX are the primary parameters of small airway function
[9,10]. Studies have shown that the IOS parameter R5-20 indicates the
severity of asthma in children [24], predicts future asthma attacks [25],
and can be used to assess asthma control [10]. Shiet al. conducted a
study of 6- to 17-year-olds and showed significant differences among
controlled, uncontrolled, and healthy groups with regard to the IOS
parameters R5-20, X5, Fres, and AX. The AUCs were 0.86 for R5-20 and
0.84 for AX for assessing asthma control [10]. This study showed that
R5-20, AX, R5, and X5 were significantly higher in the uncontrolled
group than the controlled and healthy groups. Among the small airway
function parameters R5-20, AX, and X5, only X5 showed a satisfactory
predictive value for asthma control, with an AUC of 0.751 (ROC ana-
lysis). X5 is defined as the resistance value of the respiratory system at
5 Hz, and its reciprocal indicates pulmonary compliance. Shin et al.
used symptom improvement, drug use, and oral steroids to assess the
severity of asthma in preschool children. The results showed that the
IOS parameter X5 was a useful parameter to assess the severity of
asthma (intermittent or persistent) [26]. This study used the Guidelines
for the Diagnosis and Treatment of Childhood Bronchial Asthma (2008)
and the same criteria described above to assess asthma control. The
results showed that X5 was a useful parameter to assess asthma control
among preschool children. Clinical experience shows that after an
asthma attack subsides, airway resistance decreases, and the para-
meters R5, X5, and Fres improve; in fact, X5 and Fres are the first

Table 2
FeNO and IOS parameters for the controlled, uncontrolled, and healthy groups.
Asthma Status P p

Healthy (n = 25) Controlled (n = 27) Uncontrolled (n = 52) Healthy vs controlled Health vs uncontrolled Controlled vs uncontrolled

## ##
FeNO 16.96 ± 11.588 17.63 ± 7.354 36.40 ± 21.07 0.883 < 0.001 < 0.001## < 0.001#
AX 26.15 ± 7.534 32.16 ± 8.436 38.34 ± 13.563 0.027## < 0.001## 0.044## 0.001#
R5-20 3.52 ± 1.311 4.54 ± 1.237 5.36 ± 1.545 0.033&& < 0.001&& 0.047&& < 0.001&
R5 9.97 ± 1.576 10.48 ± 1.806 11.41 ± 2.029 0.322## 0.002## 0.04## 0.005#
R20 63.61 ± 15.455 64.19 ± 17.684 69.69 ± 19.520 0.726&& 0.522&& 0.621&& 0.274&
X5 −3.85 ± 0.572 −3.89 ± 1.054 −5.07 ± 1.554 0.923## < 0.001## < 0.001## < 0.001#
Fres 19.74 ± 1.851 20.39 ± 1.612 20.73 ± 2.277 0.794&& 0.14&& 1&& 0.137&

Note: FeNO (ppb), AX (cmH2O/l), R5-20 (cmH2O/[l/s]), R5 (cmH2O/[l/s]), R20 (cmH2O/[l/s]], X5 (cmH2O/[l/s]), Fres (l/s). In the upper right corner of P value: "&
" is the representative of F test; "&&" is the representative of Bonferroni test; "#" is the representative of Welch approximate F test; "##" is the representative of
Dunnett's T3 test.

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J. Zeng et al. Respiratory Medicine 145 (2018) 8–13

Fig. 1. Statistical chart of differences in FeNO,IOS examination between control group, uncontrolled group and healthy group.

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J. Zeng et al. Respiratory Medicine 145 (2018) 8–13

Fig. 2. The ROC curve of FeNO combined with the IOS parameter X5 for asthma control group.

Table 3 peripheral airways, even alveolar inflammation [12]. Keen et al. con-
The AUC of each IOS parameter, FeNO, and ducted a study of children with asthma aged 6 to 18 and showed that
FeNO combined with each IOS parameter. FeNO reflects bronchial hyperresponsiveness and is closely related to
Variable AUC small airway function [27]. Small airway function is associated with
asthma control. However, researchers continue to debate the relation-
FeNO 0.783 ship between FeNO and asthma control. A study of children with
AX 0.636
asthma in Vietnam showed that FeNO was an appropriate and useful
R5 0.624
R20 0.535 tool for assessing asthma control [15]. Two other studies showed that
R5-20 0.631 FeNO was significantly reduced as asthma symptoms became controlled
X5 0.751 through a steroid treatment [28,29]. However, Thomas et al. conducted
Fres 0.517 a study of school-age children and adolescents with asthma and showed
FeNO + X5 0.866
that asthma control was unrelated to FeNO [30], which was further
supported by several other studies conducted among children aged 6
parameters to return to normal. Shi et al. showed that R5-20 and AX are years or older [31,32]. On the other hand, the current study showed a
useful parameters to assess asthma control [10], which differed from significant difference in FeNO between the controlled group and the
the findings of this study. This discrepancy might be related to the uncontrolled group of preschool children with asthma; however, the
different study populations because the current study was conducted ROC analysis showed that the AUC was only 0.786 for FeNO alone.
among preschool children with mild-to-moderate asthma whose ana- Liu et al. [14] showed that FeNO combined with IOS better assesses
tomical features and physiological lung function differed from those of the small airway function of patients with asthma, with high sensitivity
children aged 5 years and older. and specificity. Asthma control is closely related to small airway
FeNO is a biomarker of reactive airway inflammation, especially function. Successful asthma control is related to a decrease in the
airway eosinophilic inflammation. FeNO reflects both the central and airway inflammatory response, whereas FeNO reflects airway

Table 4
The AUC of FeNO combined with X5 or AX.
Cut-off value Sensitivity Specificity Youden index

X5[cmH2O/(l/s)] −3.60 0.98 0.51 0.50

FeNO(ppb) 27 0.63 0.93 0.56
X5[cmH2O/(l/s)]+FeNO (ppb) −3.60,27 0.81 0.74 0.55

12
J. Zeng et al.
inflammation, especially eosinophilic inflammation. As such, we used
both IOS and FeNO to assess asthma control. The results showed that
the AUC was 0.866 for FeNO combined with X5, which suggests that
FeNO (cut-off value: 27) combined with X5 (cut-off value: −3.60) was
better for assessing asthma control.
4. Limitations
Studies of adults with asthma have shown that bronchial hyperre-
sponsiveness, airway inflammation, and even airway remodelling can
still occur in patients with adequate clinical control [33,34]. This study
investigated the relationship between asthma control among preschool-
age children and FeNO and IOS parameters; however, we did not in-
vestigate bronchial hyperresponsiveness. Moreover, the sample size was
small; thus, conclusions must be further validated with larger sample
sizes. In addition, this study was conducted in children with mild-to-
moderate asthma, and children with severe asthma were excluded.
More research is needed to confirm whether the current conclusions
apply to children with severe bronchial asthma.
5. Conclusion
The ROC analysis showed that the AUC was 0.866 for FeNO (cut-off
value: 27) combined with X5 (cut-off value: −3.60), suggesting that
regular monitoring of FeNO and IOS helps to assess asthma control
among preschool-age children.
Declarations of interest
None.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (81570022).
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