Sugawara et al. Respiratory Research(2020) 21:226
https://doi.org/10.1186/s12931-020-01494-x

RESEARCH

Open AccessA retrospective analysis of usefulness of
impulse oscillometry system in thetreatment of asthma
Hiroyuki Sugawara1,2, Atsushi Saito2* , Saori Yokoyama2, Kazunori Tsunematsu1, Hirofumi Chiba2 andHiroki Takahashi2

Abstract
Background: Bronchial asthma (BA) has different phenotypes, and it requires a clinically effective subtypeclassification system. The impulse oscillometry system (IOS) is an emerging technique device used in respiratory
functional tests. However, its efficacy has not been validated. Therefore, this study aimed to assess the relationshipbetween BA and the IOS parameters, and the difference in the therapeutic effects of inhaled corticosteroids (ICSs)
among the subtype classifications was evaluated using the IOS.
Methods: Of the 245 patients with bronchial asthma who were screened, 108 were enrolled in this study. Thesepatients were divided based on three subtypes according to the IOS result as follows: central predominant type(n = 34), peripheral predominant type (n = 58), and resistless type (n = 16). Then, the following ICSs were randomly
prescribed in daily medical care: coarse-particle ICS (fluticasone propionate [FP]), fine-particle ICS (mometasone
furoate [MF]), and moderate-particle ICS (budesonide [BUD]). The treatment effects were assessed using the Asthma
Health Questionnaire (AHQ) and the Asthma Control Test (ACT) and were compared among the three subtypes.
Results: In the central predominant type, the AHQ score of the MF group was significantly higher than that of the
FP group (15.4 vs. 3.6, p < 0.01) and the BUD group (15.4 vs. 8.8, p < 0.05); the ACT score of the FP group was
significantly higher than that of the MF and BUD groups (24.3 vs. 21.7, 22.3, respectively, p < 0.05) at 4 weeks after
treatment. In the peripheral predominant type, the AHQ score of the FP group was significantly higher than that of
the MF group (14.1 vs. 3.4, p < 0.05); the ACT score of the FP group was lower than that of the MF and BUD groups(22.8 vs. 24.6, 24.4, respectively, p < 0.01) at 4 weeks after treatment.
Conclusions: An association was observed between IOS subtype classification and ICS particle size in terms oftherapeutic efficacy in BA. This result indicates that the IOS could be an effective tool in the selection of ICS andthe evaluation of the BA phenotype.
Keywords: Bronchial asthma, Inhaled corticosteroids, Impulse oscillometry system, Pulmonary function test, Asthma
health questionnaire, Asthma control test

* Correspondence: a-saito@sapmed.ac.jp
2
Department of Respiratory Medicine and Allergology, Sapporo Medical
University School of Medicine, S1W16 Chuoku, Sapporo, Hokkaido 060-8543,
Japan
Full list of author information is available at the end of the article© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Sugawara et al. Respiratory Research(2020) 21:226

Background
Asthma is one of the most common chronic respiratory diseases affecting 1–18% of the population in different countries, and it is typically characterized bychronic airway inflammation. Moreover, individuals
with asthma present with variable expiratory airflow
limitation and respiratory symptoms, such as wheezing, shortness of breath, chest tightness, and cough,which vary over time and in intensity [1]. Asthma isa heterogeneous disease, and the cluster of demographic, clinical and/or pathophysiological characteristics are often referred to as asthma phenotypes [2–4].
However, clinical phenotypes or treatment responses
are not correlated to pathological features [5]. Thus,
further research should be performed to assess theclinical efficacy of a phenotypic classification system
for asthma. The impulse oscillometry system (IOS)
can be used to assess the parameters of large andsmall airway functions. Moreover, it is an emerging
technique and noninvasive device used for the assessment of respiratory function using the forced oscillation technique, which was first described by Dubois
et al. [6–8]. This device uses sound waves to rapidly
detect airway changes. These pressure signals can independently quantify the degree of obstruction in thecentral and peripheral airways. Moreover, ICSs withdifferent particle sizes are commercially available. In
asthma, therapeutic effects may differ based on the
drug aerosol’s particle size and location of inflammation [9, 10]. Our recent study revealed that a relationship exists between the therapeutic effect based on
the particle size of ICSs and the parameters of IOS in
CVA patients [11]. Using the IOS, the cough variant
asthma (CVA) subtypes were classified as follows: thecentral, peripheral, and resistless type. Coarse- andfine-particle ICSs are effective for patients with central and peripheral airway resistance, respectively [11].
IOS values are reported to more correlate with clinical symptoms in asthma compared with spirometry
as well as CVA, because it is possible to detect subtle
airway changes earlier than spirometry [12, 13]. Airway inflammation in BA may extend from the central
to the peripheral airways [14]. Thus, several studies
have assessed the clinical application of the IOS for
the treatment of BA [15, 16].
In this study, we examined the effect of dry powder inhaler (DPI) and excluded pressurized metered dose inhaler (pMDI) device because pMDI and DPI are
completely different in terms of the inhalation procedure. For instance, DPI requires a strong inspiratory flow
velocity, and breath holding after inhalation appears to
be important for pMDI.
In the current study, the clinical role of the IOS in BA
was assessed by dividing the participants according toPage 2 of 9

three subtypes with the R20 and R5 − R20 values. Moreover, whether the IOS can be utilized in the diagnosis
and therapeutic evaluation of BA was assessed.

MethodParticipants and treatments

This investigation is a single-center retrospective observational study. Patients who presented with ICS-naïve
BA and visited our clinic for the first time between April
2017 and June 2019 were included in this study. BA wasdefined as the presence of variable expiratory airflow
limitation and history of respiratory symptoms, such as
wheezing, shortness of breath, chest tightness, andcough, which vary over time and in intensity. Patients
who had respiratory symptoms and detailed history andexamination results supporting asthma diagnosis werediagnosed with asthma based on variable airflow limitation, as evidenced by reduced forced expiratory volume
in 1 s (FEV1) and FEV1/forced vital capacity (FVC) ratio,
and a significant increase in lung function 4 weeks afteranti-inflammatory treatment [1]. Patients diagnosed withbronchial asthma were treated according to the Japanese
asthma prevention and management guidelines [17].
Three ICSs were used for treatment and were randomly
assigned to the patient groups: fluticasone propionate(FP: average particle size = 4.4 um [coarse particle]),mometasone furoate (MF: average particle size = 2.0 um[fine particle]), and budesonide (BUD; average particle
size = 2.4 um [moderate particle]). In addition to the ICS
therapy, all patients were treated with salmeterol or formoterol (long-acting beta2-agonists) and montelukast(leukotriene receptor antagonists). Therapeutic efficacy
was assessed at baseline and 2 and 4 weeks after treatment using the Asthma Health Questionnaire (AHQ)33-Japan and at baseline and 4 weeks after treatment
with the asthma control test (ACT). IOS was performed
as a supplementary diagnosis for research purpose. Participants were divided into three groups according to the
IOS value after the start of the study. The experimental
protocols and the purpose of the research were explained to all participants and informed consent was obtained in the form of opt-out on the web-site. The study
was conducted in accordance with the declaration of
Helsinki and was approved by the institutional ethicalcommittee of Sapporo Medical Association.
Measurements of IOS and pulmonary function

IOS measurements were assessed using a commerciallyavailable IO device (Master Screen IOS, Jaeger,
Germany) according to the manufacturer’s recommendations [8]. The resistance at 5 Hz (R5: indicating total
airway resistance), resistance at 20 Hz (R20: representing
central airway resistance), difference between R5 andR20 (R5 − R20: index of the small airways), reactance at

Sugawara et al. Respiratory Research(2020) 21:226

Page 3 of 9

5 Hz (X5: relating to compliance), resonant frequency(Fres), and integrated area of low-frequent X (AX) values
were evaluated [18–20]. The use of Fres and AX for detecting expiratory flow limitations was proposed.
After the IOS measurement, spirometry was performed by using MasterScreen IOS-Jaeger (Germany).
To prevent the occurrence of any negative effects causedby forced expiration on the airway, spirometry was not
performed before IOS measurement. The percentage
predicted forced vital capacity (%FVC), percentage predicted forced expiratory volume in 1 second (%FEV1),
FEV1/FVC ratio, percentage predicted maximal midexpiratory flow (%MMEF), and percentage predictedpeak expiratory flow (%PEF) were assessed.
The predicted values (PV) of the parameters of IOS
were calculated using the equations reported by Vogelet al. [21]. The patients diagnosed with BA were divided
based on three subtypes, as shown in Table 1.

AHQ and ACT

All participants with asthma completed the AHQ atbaseline and 2 and 4 weeks after treatment and the ACT
at baseline and 4 weeks after treatment.
The Japanese version of the AHQ, which is a diseasespecific, health-related quality of life questionnaire, wasdeveloped [22, 23]. The clinical validity of the AHQ was
evaluated, and it was found to be reliable and effective
for discriminative purposes. Thus, it can be used withconfidence in clinical research. The AHQ has six subscales (asthmatic symptom, emotion, daily activity, factors that worsened symptoms, social activity, andeconomics) and comprises 32 items (grades 0–4) and
one face scale (grades 1–5). A higher AHQ score reflect
a worse health status with respect to these 33 items.
The ACT is a validated, patient-completed measure ofasthma control, which comprises five questions used toassess activity limitation, shortness of breath, night-time
symptoms, use of rescue medication, and overall ratingof asthma control within the last 4 weeks [24]. The questions are scored from 1 (worst) to 5 (best), and the ACTscore is obtained by obtaining the sum of the responses,
with a maximum best score of 25. An ACT score of 19
indicated the highest area under the ROC curve. Thus, ascore ≥ 20 is considered the optimal cutoff point for awell-controlled asthma within the last 4 weeks.
Measurement of FeNO

Fractional exhaled nitric oxide (FeNO) measurement
was performed according to the 2011 recommendationsof the American Thoracic Society [25] and prior to spirometry to prevent modifying its values. Niox® VERO
(Circassia AB, Sweden), a portable analyzer, was used toassess whether the expiratory flow was maintained at 50
mL/s using acoustic emission signal.
Statistical analysis

Numeric variables were expressed as means ± standard
error of mean. Differences among the groups wereassessed with non-repeated analysis of variance with orwithout the Student–Newman–Keuls test. The differences before and after treatment were compared using
paired t-test or Wilcoxon signed-rank test. Categoricalvariables were tested using the chi-square test. A p value< 0.05 was considered statistically significant. Microsoft
Excel 2007 (Microsoft Corporation, the USA), Excel
Statistical Program File (ystat2008.xls, Igakutoshoshuppan Ltd., Tokyo, Japan), and GraphPad Prism v8
software (GraphPad, Inc., San Diego, CA, the USA) wereused for data analysis and graph generation. Spearman’s
correlation analysis and JMP13.0 (SAS Institute, Cary,NC, the USA) were used to evaluate the coefficients ofdetermination (ρ), residuals, and significance (p) to identify the associations between the pulmonary function
test score and IOS index.

Results
Selection of participants

Of the 245 patients with bronchial asthma who werescreened, 137 were excluded due to a history of treatment (n = 33), asthma and COPD overlap (n = 10), andrefractory asthma (n = 3), use of ICS other than dry powder inhalation (n = 50), and dropout (n = 41). In total,
108 patients were enrolled in this study. These patientswere divided based on three subtypes according to the
IOS result, as described in the Methods section: CP type(n = 34), PP type (n = 58), and resistless type (n = 16). In
addition, these patients were randomly prescribed with

Table 1 Definition of the subtypes of bronchial asthma classified using the impulse oscillometry. The predicted values of theparameters using the impulse oscillometry system were calculated using the equations reported by Vogel et al
Central predominant (CP) type

R20

R5 − R20(R20 − PV) − ([R5 − R20] − PV)≥100%< 100%

–

≥100%

≥100%

≥0

Peripheral predominant (PP) type

< 100%

≥100%

–

≥100%

≥100%

<0

Resistless type

< 100%< 100%–

Sugawara et al. Respiratory Research(2020) 21:226

any ICS (FP, MF, or BUD) to compare the therapeutic
effects of the drug: 34 patients with the CP type (FP: 15,
MF: 9, and BUD: 10), 58 patients with the PP type (FP:19, MF: 17, and BUD: 22), and 16 patients with the resistless type (FP: 6, MF: 4, and BUD: 6) (Fig. 1).
Baseline characteristics of the participants

The characteristics of the patients are summarized inTable 2. The number of young participants in the CP
group was slightly higher than that in the other groups.
No difference was observed among the three groups interms of sex ratio, duration of disease, smoking rate,
BMI, IgE level, number of eosinophils in the peripheral
blood, and FeNO. In terms of spirometry parameters,
the %FEV1, FEV1/FVC ratio, and %MMEF of the PP
type were significantly lower than those of the CP andresistless types. The %PEF of the resistless type washigher than that of the CP and PP types. In addition, thecharacteristics of the three ICS groups are summarizedin Table S1. No statistically significant differences wereobserved in terms of characteristics among the groups.

Page 4 of 9

significantly higher than that of the FP group (15.4 vs.
3.6, p < 0.01) and BUD group (15.4 vs. 8.8, p < 0.05) at 4
weeks. In the PP type, the AHQ score of the FP groupwas significantly higher than that of the MF group (24.3
vs. 7.4, p < 0.05) and BUD group (24.3 vs. 11.4, p < 0.05)
at 2 weeks and the MF group (14.1 vs. 3.4, p < 0.05) at 4
weeks.
Therapeutic evaluation with ACT

Next, we analyzed the ACT, which is a widely used selfadministered assessment tool for determining how well apatient’s asthma is controlled. Although there was no statistically significant difference in ACT scores among thethree ICP groups in the CP type at baseline, major differences were observed after treatment. The ACT score of
the FP group was significantly higher than that of the MF
and BUD groups (24.3 vs. 21.7, 22.3, respectively, p < 0.05)
at 4 weeks after treatment. By contrast, in the PP type, theACT score of the FP group was lower than that of the MF
and BUD groups (22.8 vs. 24.6, 24.4, respectively, p < 0.01)
at 4 weeks after treatment (Fig. 2b).

Therapeutic evaluation with the AHQ

Therapeutic effects on pulmonary function and IOS

The severity of asthma symptoms and patient-related
outcome were evaluated with the AHQ, which is a simple and objective measurement tool for asthma symptoms (Fig. 2a). In the CP type, the FP group had a higher
AHQ score than the MF and BUD groups at baseline.
The AHQ score did not significantly differ among thethree ICS groups in the CP type at 2 weeks after treatment and in the PP type at baseline. By contrast, there
were significant differences among the subtypes. In the
CP type, the AHQ score of the MF group was

We examined whether the classification using the IOS
value was correlated to the clinical data before and after
treatment. FeNO is useful for the diagnosis and identification of treatment effect in asthma. In this analysis,
FeNO improved with treatment. However, no difference
was observed between the three groups. Spirometry wasan objective parameter relatively similar to IOS, and it
had a similar treatment behavior to IOS, but the difference between the three groups after treatment was not
significant in FEV1 and FVC. The IOS value itself

Fig. 1 Selection of participants. Of the 245 patients diagnosed with bronchial asthma who visited the clinic between April 2017 and June 2019,
137 were excluded and 108 participated. In total, 34 patients with central predominant type, 58 with peripheral predominant type, and 16 withresistless type were enrolled. The definition of the subtypes of bronchial asthma classified using the impulse oscillometry system is shown in
Table 1

Sugawara et al. Respiratory Research(2020) 21:226

Page 5 of 9

Table 2 Baseline characteristics of the study participants and the subgroups. Data were presented as mean (standard error of mean)or number (percentage). The differences among the subtypes were assessed using non-repeated analysis of (†P) with the Student–
Newman–Keuls test for age, duration of disease, body mass index, IgE level, number of eosinophil in the blood, and spirometricparameter (post-hoc test). The differences in sex and smoking were tested using the chi-square test. *: p < 0.05, **: p < 0.01 and NS:
not significant. CP-PP: between the central predominant type and peripheral predominant type; CP-R: between the central
predominant type and resistless type; and PP-R: between the peripheral predominant type and resistless typeAll

Subtypes
CP

PP

R

108

34

58

16

Age

47.9 (1.7)

41.3 (2.7)

52.0 (2.3)

Male/female (% of female)

45/64

14/20 (58.8)

19/39 (67.2)

Duration of disease (years)

4.9 (0.7)

5.1 (1.3)

Smoker/non-smoker (% of smokers)

68/40

20/14 (58.8)

BMI

25.3 (0.5)

Total IgE level (IU/mL)

410.0 (60.4)

Eosinophil in the blood (/μl)
FeNO (ppb)nPost-hoc test
P

CP-PP

CP-R

PP-R

50.0 (4.0)

*

*

NS

NS

11/5 (31.1)NS

5.4 (0.8)

2.4 (0.7)

NS37/21 (63.8)

11/5 (68.8)

NS

25.6 (0.9)

25.6 (0.6)

23.8 (1.0)

NS

440.1 (138.8)

389.9 (79.9)

426.7 (87.0)

NS

278.4 (18.9)

227.6 (138.9)

306.4 (22.4)

271.4 (36.1)

NS

71.0 (5.8)

54.9 (9,7)

72.4 (8.0)

100.0 (13.0)NS

80.9 (1.7)

82.6 (2.9)

77.0 (2.4)

91.0 (2.3)

**

NS

NS

*

Characteristics of the patients

Spirometric values% FVC% FEV1

67.3 (1.9)

72.4 (3.1)

61.4 (2.7)

77.9 (2.0)

**

*

NS

**

FEV1/FVC ratio

69.4 (1.1)

75.1 (1.9)

65.2 (1.5)

72.8 (2.3)

**

**

NS

*

%MMEF

33.9 (2.0)

43.8 4.0)

26.1 (2.1)

41.3 (4.2)

**

**

NS

**

% PEF

73.1 (2.4)

74.2 (3.5)

66.4 (3.4)

95.3 (4.0)

**

NS

**

**

significantly improved with treatment in all groups, but
unlike the respiratory function test values, the difference
between the three groups was still observed even after
treatment, indicating that IOS may be more effective inreflecting airway impairment (Table 3). When the IOS
and respiratory function test results of the participants
were compared (Table 4), most items were found to becorrelated. However, no significant association was observed between most spirometric value and R20, which
is an indicator of the central airway function, and only
%PEF was correlated to the IOS value.

Discussion
The current study showed that the differences in asthma
phenotypes based on the IOS parameters might be correlated to the efficacy of ICSs. Moreover, IOS was significantly correlated to the severity of asthma. Our
previous study has revealed that the phenotypic differences in IOS parameters were associated with the efficacy of ICSs in CVA patients [11]. Thus, we examined
the role of IOS in BA in this study. Based on the observation of IOS, it became clear that the phenotypes of BA
predominating in central airway lesions and BA predominating in peripheral airway lesions exist. According to
the result, the participants were divided based on threesubtypes, which were as follows: the CP, PP, and R types.

In terms of background characteristics, the participants
did not significantly differ (Table 2). However, the age ofthe participants with the CP type was lower than that ofparticipants with the PP and R type. This result may reflect that age at onset in the CP type was earlier thanthat in the PP type. The spirometry values differed atbaseline in the three groups. The %FEV1, FEV1/FVC,
and %MMEF of the PP type were lower than those of
the CP and R types (Table 2). Some studies showed thatthe small airways were the major site of inflammationand obstruction in asthma [26–31]. Thus, we believedthat the PP type may be more severe than the CP and R
types. Moreover, IOS is a useful device used for the simultaneous assessment of diseases in the peripheral andlarge airways. Therefore, the role of IOS in BA therapy
was examined in this study, which first reported about
the subtype of bronchial asthma using IOS. The efficacy
of FP and BUD was highest in the CP type. In the PP
type, the AHQ score decreased in the MF group compared with FP group (Fig. 2a). Regarding the ACT in the
CP type, the score of the FP group was significantly
higher than that of the MF group. In the PP type, theACT score of the FP group was significantly lower thanthat of the MF group (Fig. 2b). These results indicatethat ICSs with coarse- and fine particles are most suitable for the CP and PP type, respectively. Considering

Sugawara et al. Respiratory Research(2020) 21:226

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Fig. 2 Comparison of the Asthma Health Questionnaire score (a) and asthma control test results (b) among the ICS therapy groups in terms ofsubtypes at baseline and after treatment. ICS: inhaled corticosteroid; FP: fluticasone propionate; MF: mometasone furoate; and BUD: budesonide.
The bars were expressed as mean ± standard error of mean. The differences among the ICS group were analyzed using the non-repeated analysis
of variance with the Student–Newman–Keuls test. *: p < 0.05, **: p < 0.01

these results, the differences in phenotypes based on
the IOS parameters might be correlated to the efficacy of ICSs. Thus, IOS examination should be performed on patients with BA prior to ICS
administration, and it is better to use ICS with acoarse-particle size for the CP type and ICS with afine-particle size for the PP type.
The deposition of different sized particles in central
versus peripheral airways is controversial. Baou EL reported that in a meta-analysis of studies on patients withasthma, no significant differences were observed between smaller size and larger standard size particle of
ICS for change in spirometry. Although there was a relationship between smaller particle size and increased delivery to the distal lung, increased deposition in the
distal lung did not improve the clinical outcomes inpatients with asthma [32]. On the other hand, this study
indicated that there may be a certain relationship between the site of airway impairment and the particle sizeof ICS. In considering the impact of ICS with different
particle sizes, we believe that it could be important tounderstand the factors influencing the pattern of deposition of an aerosol in the airway and alveolar compartment. The existing tools used to evaluate central andperipheral airway function such as sputum induction(early or late phase sputum), high-resolution computed
tomography (airway thickness or air trapping), and exhaled nitric oxide (bronchial or alveolar eNO) are noteasier methods in outpatient assessment of peripheral
and central airway parameters than IOS. Therefore, we
consider IOS to be a useful tool in the treatment ofasthma.

Sugawara et al. Respiratory Research(2020) 21:226

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Table 3 Comparison between the impulse oscillometry system and spirometry in terms of subtypes at baseline (pre) and after
treatment (post)
All

Subtypes

P

CP

PP

R

54.9

72.4

93.1

NS
NS

Post-hoc test
CP-PP

CP-R

PP-R

FeNO (ppm)
Pre
Post

70.6
28.8

27.4

26.7

31.9

**

*

**

**

0.46

0.44

0.53

0.25

**

**

**

**

**

NS

**

**

Impulse oscillometry
R5 (kPa/L/s)

Pre
Post

R20

R5-R20

Fres

0.33

0.22

**

NS

Pre

0.31

0.37

0.30

0.22

**

**

**

**

0.26

0.30

0.25

0.19

**

**

**

**

**

**

**

NS

0.15

0.07

0.23

0.03

**

**

NS

**

**

**

NS

**

Pre

0.06

0.04

0.08

0.02

**

NS

**

NS

Pre

−0.24

−0.16

−0.33

−0.12

**

**

NS

**

Post

−0.12

−0.12

−0.13

−0.09

*

NS

NS

*

**

**

**

**

19.8

15.7

24.0

14.0

**

**

NS

**

**

*

NS

**

Pre
Post

AX

0.33
**

Post

Post

X5

0.31
**

14.2

12.2

15.9

11.4

**

**

**

*

Pre

1.84

0.81

2.91

0.39

**

**

NS

**

Post

0.54

0.38

0.69

0.24

**

*

NS

**

**

**

**

*

NS

NS

**

*

NS

**

Spirometric values
%FVC

%FEV1

Pre

80.9

82.6

77.0

91.0

*

Post

99.0

97.8

99.2

100.4

NS

**

**

**

*

67.5

72.4

61.4

77.9

**
NS

Pre
Post

FEV1/FVC ratio

%MMEF

94.2

91.2

95.2

**

**

**

Pre

69.6

75.1

65.2

72.8

**

**

NS

*

Post

78.9

81.9

77.0

80.3

*

*

NS

NS

**

**

**

**

34.0

43.8

26.1

41.3

**

**

NS

**

*

NS

NS

NS

Pre
Post

%PEF

92.7
**

61.0

67.9

55.5

68.2

**

**

**

**

Pre

73.1

74.2

66.4

95.3

**

NS

**

**

Post

103.9

100.9

102.4

115.3

*

NS

*

**

**

**

**

**

Data were presented as mean (standard error of mean) or number (percentage). The differences among the subtypes were evaluated using non-repeated analysis
of variance (†P) with the Student–Newman–Keuls test. *: p < 0.05, **: p < 0.01 and NS: not significant. CP-PP: between the central predominant type and peripheral
predominant type; CP-R: between the central predominant type and resistless type; and PP-R: between the peripheral predominant type and resistless type

Sugawara et al. Respiratory Research(2020) 21:226

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Table 4 Correlation between impulse oscillometry system and spirometric parameters without grouping
R5R20
R5 − R20
X5

Fres

AX

%FVC

%FEV1

FEV1/FVC ratio

%MMEF

%PEF

r

0.3

0.42

0.46

0.45

0.54

P

0.0013**

5.3E–06**

6.9E–07**

7.8E–07**

2.3E–09**

r

0.02

0.06

0.07

0.11

0.27

P

0.85

0.54

0.44

0.24

0.005**

r

0.36

0.52

0.58

0.54

0.52

P

0.0005**

1.2E–08**

9.0E–09**

2.9E–09**

6.9E–09**

r

0.51

0.62

0.61

0.54

0.64

P

2.3E–08 **9.9E–13**

1.2E–12**

1.8E–09**

9.0E–14**

r

0.45

0.61

0.65

0.6

0.55

P

8.6E–07**

2.2E–12**

4.4E–14**

4.1E–10**

6.7E–10**

r

0.47

0.61

0.62

0.55

0.61

P

2.2E–07**

4.1E–12**

5.7E–13**

6.5E–10**

3.3E–12**

Data were presented as the Pearson correlation coefficient (r) and p-value (P) via a linear regression analysis. **: p < 0.01

When we reconsidered the patient group using the
IOS values, we focused on a group called the whole airway type, which was characterized by high R20 and highR5 − R20 (Table S2). This group had the lowest spirometry value, the highest AHQ score, and the lowest ACTscore. The whole airway type is believed to present with
inflammation or remodeling in both the central and peripheral airways. As previously mentioned, coarse-particle
ICSs are suitable for CP type and fine-particle ICSs for
PP type. Thus, if a patient with refractory asthma havehigh R20 and R5 − R20, combination therapy withcoarse- and fine-particle ICSs should be considered.
The current study had some limitations. Since IOS isan emerging technique, data about the exact meaning,interpretation, and clinical application of IOS parameters
versus spirometric parameters are limited. The reference
values used in this study are based primarily on data obtained from Caucasians, and they might cause bias when
adapted in Japanese. Asthma that is refractory to ICS
will be excluded, but it is difficult to include it in thisstudy because such cases have not been diagnosed withasthma. Several ICSs are randomly prescribed by multiple physicians in their routine asthma treatment practice. However, some bias might exist in the prescriptionof ICS. Furthermore, the follow-up period in the current
study was short. This study was a retrospective observational research assuming no difference between salmeterol and formoterol, but the results must be confirmed
in a prospective study, and moreover, the aerosol types
of ICS were not examined. Thus, further research must
be conducted to identify the most effective individualized treatment for BA using IOS.

Conclusions
The effect of treatment with ICSs and their correlation
to the parameters of IOS in patients with BA were

investigated. The phenotypic differences in IOS parameters might be associated with the efficacy of ICSs. Thatis, coarse-particle ICSs were found to be effective for patients with central airway resistance and fine-particle
ICSs for those with peripheral airway resistance. In
addition, IOS could detect the diversity in airway dysfunction, thereby indicating its efficacy considering thatthe lesion sites are the central and peripheral airways.
Hence, we recommend the use of IOS in the examination of BA before ICS administration. Moreover, IOS
was effective when used in the selection of ICS and theevaluation of the BA phenotype.

Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s12931-020-01494-x.
Additional file 1: Table S1. Comparison of characteristics among ICS
groups in BA subtypes at baseline. Data were presented as mean
(standard error of mean) or number (percentage). Definition ofabbreviations are same as indicated in Table 2. Table S2. Data were
presented as mean (standard error of mean). Differences between thewhole type and other type were analyzed by a paired t-test (†P). *:p < .05, **: p < .01 and NS: no significant.
Abbreviations
IOS: Impulse oscillometry system; AHQ: Asthma Health Questionnaire;
ACT: Asthma control test; ICS: Inhaled corticosteroid; FVC: Forced vital
capacity; FEV1: Forced expiratory volume in 1 s; MMEF: Maximum midexpiratory flow; PEF: Peak expiratory flow; R5: Resistance at 5 Hz;
R20: Resistance at 20 Hz; R5 − R20: Resistance at 5–20 Hz; X5: Reactance at 5
Hz; Fres: Resonance frequency; AX: Area of low-frequency reactanceAcknowledgments
Not applicable.
Authors’ contributions
HS developed the study design, performed the experiments, analyzed andinterpreted the data, and wrote the manuscript. AS contributed to data
analysis and interpretation and manuscript revision. SY, KT, HC, and HT
assisted with data analysis and interpretation and supervised the statisticalanalysis. The authors read and approved the final manuscript.

Sugawara et al. Respiratory Research(2020) 21:226

Funding
This work was supported by Novartis Pharma Research Grants 2019 (to A. S.)
and JSPS KAKENHI Grant Numbers 19 K23610 (to S. Y.).
Availability of data and materials
Please contact author for data requests.
Ethics approval and consent to participate
The study was approved by the ethics board of Sapporo Medical
Association.
Competing interests
None of the authors have a conflict of interest to declare.
Author details
1
Sugawara Internal Medicine and Respiratory Clinic, Tomakomai 053-0821,
Japan. 2Department of Respiratory Medicine and Allergology, Sapporo
Medical University School of Medicine, S1W16 Chuoku, Sapporo, Hokkaido
060-8543, Japan.
Received: 9 April 2020 Accepted: 23 August 2020

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