Sugawara et al. Respiratory Research(2019) 20:41
https://doi.org/10.1186/s12931-019-1005-2

RESEARCH

Open AccessComparison of therapeutic effects ofinhaled corticosteroids on three subtypesof cough variant asthma as classified by
the impulse oscillometry system
Hiroyuki Sugawara1,2, Atsushi Saito2,3* , Saori Yokoyama2, Kazunori Tsunematsu1 and Hiroki Takahashi2

Abstract
Background: Cough variant asthma (CVA) is one of the most common causes of chronic persistent cough, andearly treatment with inhaled corticosteroids (ICSs) is recommended to attenuate the inflammation and remodeling.
The impulse oscillometry system (IOS) is a novel device for respiratory functional assessment that has not yet beenassessed in terms of CVA. Therefore, we investigated the relationship between CVA and IOS, and the difference intherapeutic effects of ICSs among the subtype classifications by IOS.
Methods: 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]).
Treatment effects were assessed by the Leicester cough questionnaire (LCQ) and were compared among three
separated subtypes based on IOS measurements: central, peripheral, and resistless.
Results: Regarding LCQ scores, in the central type, the LCQ of the MF group was significantly lower than FP and
BUD. In the peripheral type, the LCQ of the FP group was significantly lower than MF and BUD. In the resistless
type, the LCQ of the MF group was significantly lower than BUD. Also, IOS factors were improved by 4 weeks oftherapy with ICS. Thus, there was strong relationship between subtypes and particle size in terms of effectiveness.
Conclusions: There is a strong relationship between IOS subtype classification and ICS particle size in terms oftherapeutic efficiency in CVA. It appears important to determine the ICS particle size, based on the IOS subtypeclassification, before treatment.
Keywords: Chronic cough, Cough variant asthma, Inhaled corticosteroids, Impulse oscillometry system, Pulmonary
function test

Background
Cough is a very common complaint among patients withrespiratory problems. Based on the duration of thecough, it is classified into persistent cough (more than 3
weeks, but less than 8 weeks) and chronic cough (8weeks or longer). In Japan, it is reported that cough variant asthma (CVA) is the most common cause of chronic
persistent cough, followed by sinobronchial syndrome,* Correspondence: a-saito@sapmed.ac.jp
2
Department of Respiratory Medicine and Allergology, Sapporo Medical
University School of Medicine, Sapporo, Hokkaido 060-8543, Japan3
Department of Biochemistry, Sapporo Medical University School of
Medicine, Sapporo 060-8556, Japan
Full list of author information is available at the end of the article

gastroesophageal reflux disease, atopic cough, and postinfectious cough [1–6]. To reach a final diagnosis of prolonged chronic cough, it is important to verify the initial
therapies based on the patient’s history and laboratory
data. However, it is not easy to diagnose the cause of
cough and to select the best therapy in the clinic, given
there is currently no gold standard for diagnosis. Spirometry is frequently used in respiratory medicine;
however, it appears not to work as well for prolonged
chronic cough, including CVA, as it does for asthma andchronic obstructive pulmonary disease. Thus, we focusedon the impulse oscillometry system (IOS) as a result of
the question that the treatment efficacy varies based on© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Sugawara et al. Respiratory Research(2019) 20:41

the measured value of IOS when examining patientswith CVA in outpatient clinics. IOS, originally describedby Dubois et al. [7], is a novel, noninvasive device forrespiratory functional assessment using the forced oscillation technique. IOS uses sound waves to detect airway
changes rapidly; these pressure signals separately quantify the degree of obstruction in the central and peripheral airways. In addition, IOS can determine respiratory
resistant (R) and respiratory reactance (X) of both airways. Like spirometry, IOS values correlate with clinicalsymptoms and asthma control. Hence, we consider IOS
a useful examination method to elucidate the conditionof CVA. However, compared with spirometry, IOS is nota standard method as it is not used in many hospitals.
Thus, this study aims to use IOS as a criterion for selecting the treatment method or evaluating the treatment
effect for CVA.
Eosinophils are reportedly increased in the sputum,
bronchoalveolar lavage (BAL) fluid, and bronchial mucosal tissue of patients with CVA, and the increase in eosinophils correlates with disease severity [7, 8]. Additionally,studies on biopsy specimens of central airway mucosa and
BAL fluid recovered from peripheral airways and parenchyma have revealed that the degree of eosinophilia issimilar between classic asthma and CVA [8]. Given CVA
involves structural changes, such as subepithelial thickening, goblet cell hyperplasia, and vascular proliferation
causing airway remodeling, CVA is considered to be a peripheral airway inflammatory disease similar to asthma [8].
Some cases of CVA will evolve into continuous asthma.
Therefore, the early usage of inhaled corticosteroids (ICSs)
is recommended as CVA treatment to attenuate theinflammation and remodeling. Recently, several particle
sizes of ICS have been made commercially available. Somevariation in therapeutic effect based on the particle size
and the location of the inflammation has been suggested
in asthma [9, 10]. On the other hand, which ICS particle
sizes should be used for CVA treatment is a subject of
debate. Therefore, we decided to examine the correlation
between IOS and the therapeutic effect of ICS. IOS can beused to assess the parameters of large and small airways,
and IOS values correlate better with clinical symptoms inasthma compared with spirometry [11] because IOS candetect subtle airway changes earlier than spirometry can[12]. Although the inflammation of the airways in CVA
appears to extend from the central to the peripheral
airways, [13] few studies have assessed the clinical application of IOS for the treatment of CVA. Respiratory system
resistance at 5 Hz (R5) depicts general obstruction in boththe central and peripheral airways, as lower vibration
frequencies can be transmitted more distally in the lungs
compared with higher frequencies. Conversely, the resistance of the respiratory system at 20 Hz (R20) is considered
indicative of only the central airway, while the difference

Page 2 of 10

between R5 and R20 (R5–R20) is considered indicative of
only the peripheral airway. Some studies have reported
that the interpretation of the difference (R5–R20) between
respiratory resistance (Rrs) values at 5 and 20 Hz remains
debatable [14]. However, in this study, we analyzed by dividing participants into three groups with R20 and R5–R20
values, described above, to elucidate the discussion points.
Thus, patients with CVA were classified into three subtypes: (a) high R20 type, which was defined as the central
airway type; (b) high R5–R20 type, which was defined as
the peripheral airway type; and (c) the type that neither
R20 and R5–R20 is high, which was defined as the resistless airway type. Therefore, in this analysis, we investigated the clinical role of IOS in CVA using this subtypeclassification, including its utility as a tool for diagnosis
and therapeutic evaluation, and the relationship between
IOS values and ICS particle size.

Methods
Patients and treatments

This was a single-center, retrospective observational
study at the Sugawara Internal Medicine and Respiratory
Clinic in Japan. Based on medical record, all the consecutive and unselected patients with chronic persistent
cough visited on the clinic between September 2015 andDecember 2016 were included. Chronic persistent coughwas defined as a cough lasting more than 3 weeks without specific cause. In order to select the CVA patients,
patients with postinfectious cough, GERD-associatedcough, allergic rhinitis, atopic cough and bronchialasthma were excluded. Also, due to not continuing treatment in order to some reasons or diagnosed as otherdiseases after treatment, these patients dropped out.
Several type of ICS were randomly prescribed by multiple physicians in daily medical care according to theJapanese Respiratory Society cough guidelines [3] as follows: fluticasone propionate group (FP: average particle
size 4.1 μm [coarse particle]), mometasone furoate group(MF: average particle size 1.5 μm [fine particle]), or
budesonide group (BUD: average particle size, 2.4 μm[moderate particle]) or others. Patients treated with ICS
except for FP, MF, and BUD were excluded from thisanalysis because of small number. In addition to ICS
treatment, all the patients were treated with salmeterolor formoterol (long-acting beta2-agonists [LABA]) andmontelukast (leukotriene receptor antagonists [LTRA]).
Therapeutic efficacy was assessed by the Leicester coughquestionnaire (LCQ) at the baseline, 2 weeks, and 4
weeks after treatment. The study conformed to theprinciples outlined in the declaration of Helsinki andwas performed with the approval of the institutional ethics committee of Sapporo Medical Association. Informed
consent was obtained in the form of opt-out on the
web-site.

Sugawara et al. Respiratory Research(2019) 20:41

Measurements of IOS and pulmonary function

IOS measurements were obtained using a commerciallyavailable IO device (Master Screen IOS, Jaeger,
Germany) according to the manufacturer’s recommendations [15]. The following values were obtained: resistance at 5 Hz (R5: indicates total airway resistance);
resistance at 20 Hz (R20: approximates central airway resistance); the difference between R5 and R20 (R5-R20:
considered to be an index for small airways); reactanceat 5 Hz (X5: relates to compliance); resonant frequency(Fres); and integrated area of low-frequency X (AX)values [16–18]. Fres and AX are values that detect
expiratory flow limitations.
After the IOS measurements, the MasterScreen
IOS-Jaeger (Germany) device was used to perform spirometry. To avoid any negative effects of forced expiration on the airway, spirometry was never performed
before the IOS measurements. The percent predicted
forced vital capacity (%FVC), the percent predicted
forced expiratory volume in 1 s (%FEV1), the FEV1/FVC
ratio, the percent predicted the maximal mid-expiratory
flow (%MMEF), and the percent predicted peak expiratory flow (%PEF) were obtained.
Equations reported by Vogel et al., given below, wereused to calculate the predicted values of the IOS resistances: woman R = (3.14 + 0.0167 × age – 0.0403 ×
frequency) × 0.1 [kPa × l/s], men R = (2.4705 + 0.0109 ×
age – 0.02675 × frequency) × 0.1 [kPa × 1/s] [19]. Patientswith diagnosed clinical CVA were divided into threegroups as follows: the central type was defined as ≥100%of predicted R20 and < 100% predicted R5-R20. The
peripheral type was defined as < 100% of predicted R20
and ≥ 100% of predicted R5-R20. The resistless type wasdefined as < 100% of predicted R20 and < 100% predicted
R5-R20.
LCQ score

LCQ is a questionnaire for the assessment of the Quality of Life in patients with chronic persistent cough,and is composed of three domains (Physical: 8 questions; Psychological: 7 questions; Social: 4 questions),
and includes 19 items with a 7-point Likert response
scale. LCQ takes 5–10 min to complete. Each item assesses symptoms, or the impact of symptoms, over thelast 2 weeks on a 7-point Likert scale. Scores in threedomains are calculated as the mean for each domain(range: 1–7). The total score (range: 3–21) is calculated
by adding the domain scores together. High scores suggested a better quality of life. The questionnaire itself
can be referred to in the previous paper [20]. This tool
is brief, simple to administer, repeatable, and well validated. In this analysis, patients responded to the LCQ
questionnaire while waiting for the consultation during
every visit. Usage of the Japanese version of the LCQPage 3 of 10

has been approved by Surinder Birring, Akio Niimi, andHaruhiko Ogawa [21].
Statistical analysis

The statistical analysis was performed on the basis of an
intention-to-treat strategy. Numeric variables wereexpressed as means ± SEM. The differences between
groups were tested by nonrepeated ANOVA with or without the Student–Newman–Keuls test. Comparison of differences before and after treatment was tested by a paired
t-test or a Wilcoxon signed-rank test. Categorical variables
were tested by the chi-squared test. A P-value less than
.05 was considered statistically significant. Microsoft Excel
2007 (Microsoft Corporation, USA), the Excel Statistical
Program File (ystat2008.xls, Igakutosho-shuppan Ltd.,Tokyo, Japan), and GraphPad Prism v7 software (GraphPad, Inc., San Diego, CA, USA) were used for the data
analysis and graph generation. Spearman’s correlation
analysis and JMP13.0 (SAS Institute, Cary, NC, USA) wereused to evaluate the coefficients of determination (ρ),
residuals, and significance (p) to identify associations
between pulmonary function tests and IOS indices.

Results
Patient selection

Of 264 patients with persistent chronic cough screened,some patients were excluded with the exclusion criteria
1 and 2 as showed in Fig. 1. These patients were randomly treated with some kinds of ICS (FP, MF, BUD andothers) with moderate dose. To compare the therapeutic
effects of ICS on each IOS subtype as described below,
the patients treated with small number of ICS except for
FP, MF and BUD were also excluded. Finally, 127 patients who diagnosed as having CVA were enrolled inthis analysis. Based on the results of the IOS, we divided
the patients into three subtypes: central type (33 patients), peripheral type (35 patients), and resistless type(59 patients). The breakdown of ICS treatment was asfollows; Central type (FP: 12, MF: 11, BUD: 10 patients,
respectively), Peripheral type (FP: 10, MF: 16, BUD: 9
patients, respectively) and Resistless type (FP: 13, MF:
11, BUD: 35 patients, respectively) (Fig. 1).
Baseline characteristics

Table 1 summarizes the characteristics of the patients.
Compared with the other types, the patient’s age tended
to be slightly lower in the central type. The peripheral
types were more common among women and nonsmokers, and they had higher BMI values. On the other
hand, men and smokers tended to be more common in
the resistless type. Although no difference among thesubtypes was observed in terms of %FVC, %FEV1,%MMEF and LCQ scores, the peripheral type had lower
FEV1/FVC values compared with the central type, andSugawara et al. Respiratory Research(2019) 20:41

Page 4 of 10

Fig. 1 Flowchart. From 264 patients with persistent chronic cough, 127 patients with cough variant asthma participated in this analysis. A final
total of 33 patients with central type, 35 patients with peripheral type, and 59 patients with resistless type were enrolled

Table 1 Baseline characteristics of the study patients
All
n

127

Subtypes

Post-hoc test

CentralPeripheral

Resistless

33

35

59

†

P

C-P

C-R

P-R

*

*

NS

Patient characteristicAge45.7 (1.4)

39.4 (2.7)

50.4 (3.0)

46.7 (2.7)*

Male/Female (% Female)

46/81 (63%)

10/23 (70%)

3/32 (91%)

33/26 (44%)**

Atopy/Non-atopy (% Atopy)

56/50 (53%)

14/12 (53%)

14/19 (42%)

28/19 (59%)

Duration of disease (Week)

5.3 (0.3)

5.6 (0.8)

5.0 (0.5)

5.2 (0.7)

Smoker/Non-smoker (% Smoker)

52/75 (41%)

11/22 (33%)

10/25 (29%)

31/28 (53%)*

BMI

24.4 (0.4)

23.6 (0.7)

26.2 (0.8)

23.7 (0.7)

**

*

NS

*

%FVC

103.4 (1.1)

100.6 (2.3)

104.0 (2.0)

105.0 (1.6)%FEV1

101.7 (1.1)

99.4 (2.2)

101.9 (2.3)

103.1 (1.4)

FEV1/FVC

83.5 (0.5)

85.3 (1.2)

81.7 (0.8)

83.5 (0.8)

*

*

NS

NS

**

NS

**

*

Spirometry%MMEF

78.6 (1.9)

80.7 (4.0)

73.0 (3.4)

82.9 (2.5)%PEF

107.6 (1.4)

100.8 (2.3)

105.6 (3.0)

112.4 (1.8)

Total LCQ score11.8 (0.2)

12.1 (0.5)

11.6 (0.4)

11.8 (0.3)

The data are shown as mean (SEM) or number (percentage). Differences among subtypes were tested by nonrepeated ANOVA (†P) with the Student–Newman–
Keuls test for age, duration of disease, BMI, and spirometry (Post-hoc test). Differences in sex, atopy, and smoking were tested by the chi-squared test. Definitionof abbreviations: %FVC Percent predicted FVC, %FEV1 Percent predicted FEV1, %MMEF Percent predicted MMEF, %PEF Percent predicted PEF. *: p < .05, **: p < .01
and NS: not significant

Sugawara et al. Respiratory Research(2019) 20:41%PEF was higher in the resistless type than in the othersubtypes. Patient characteristics when divided into thethree ICS groups are summarized in Additional file 1:
Table S1. There were no statistically significant differences among the groups in spirometry values and LCQ
scores.
Therapeutic evaluation with LCQ

We evaluated the burden of cough in CVA, as well as
patient-related outcomes with the LCQ, which is a
simple and objective measure of cough. There were no
statistically significant differences in terms of the LCQ
between the three subtypes at baseline (Table 1). However, the LCQ scores after treatment in each subtype
were quite different (Fig. 2). In the central type, the LCQof the MF group was significantly lower than in the FP
group (14.4 vs. 18.6, p < .01) and the BUD group (14.4
vs. 19.6, p < .01) at 2 weeks of treatment; and the FP
group (15.6 vs. 20.5, p < .01) and the BUD group (15.6
vs. 18.3, p < .01) at 4 weeks of treatment. In the peripheral type, the LCQ of the FP group was significantly
lower than in the MF group (15.0 vs. 17.8, p < .01) andthe BUD group (15.0 vs. 17.4, p < .01) at 2 weeks of treatment; in the MF group (17.0 vs. 19.9, p < .01) and BUD
group (17.0 vs. 19.8, p < .01) at 4 weeks. In the resistless
type, the LCQ of the MF group was significantly
lower than in the BUD group (16.1 vs. 17.9, p < .05)
at 2 weeks of treatment; and in the BUD group (17.1
vs. 19.8, p < .01) at 4 weeks. These results indicatethat improvements in patient symptoms are closely
correlated with the particle size of the ICS. In other

Page 5 of 10

words, it appears possible to select an appropriate
ICS by classifying patients by IOS prior to treatment.
Therapeutic effects on pulmonary function and IOS
factors

Next, we examined whether IOS factors were related tothe therapeutic effects. Regarding pulmonary function
tests, there were no significant differences among thethree subtypes at both baseline and post-treatment,
except for %PEF (Table 2). Regarding the IOS factors,
when we analyzed all the cases together, most IOS
factors were improved at 4 weeks of therapy (Fig. 3).
Additionally, there was a strong relationship between%PEF and %R5, %R20 and X5 (Fig. 4). Analyzing each of
the three ICS groups individually, both R5 in the central
type and R5-R20 in the peripheral type were significantly
improved by treatment with any particle size of ICS. On
the other hand, small-particle ICSs such as MF and
BUD, but not FP, significantly decreased the index ofFres and AX, which appear to represent obstructive
or restrictive impairments of the distal respiratory
tract (Fig. 5). These results indicate that IOS indicesmight help us understand the effect of treatment withICSs in CVA.

Discussion
Multiple disorders cause chronic persistent cough. The
cause of cough in Japan is CVA or asthma in 36% ofcases, atopic cough in 29%, and sinobronchial syndromein 17%, as reported by Fujimura [1]; Matsumoto reports
55% of cases are due to CVA/asthma, atopic cough in

Fig. 2 Comparison of LCQ scores in the ICS therapy groups in the subtypes at the baseline (0w) and after treatment (4w). FP: fluticasone
propionate; MF: mometasone furoate; BUD: budesonide. Bars are expressed as the mean ± SEM. Differences among IOS groups were tested bynonrepeated ANOVA with Student–Newman–Keuls test. *: p < .05, **: p < .01

Sugawara et al. Respiratory Research(2019) 20:41

Page 6 of 10

Table 2 Comparison of impulse oscillometry and spirometry
over subtypes at the baseline (Pre) and after treatment (Post)
Subtypes
CentralPost-hoc test
Peripheral

Resistless

Table 2 Comparison of impulse oscillometry and spirometry
over subtypes at the baseline (Pre) and after treatment (Post)(Continued)‡

Subtypes

P C-P C-R P-R

Impulse oscillometry

0.36 (0.01)

0.36 (0.01)

0.22 (0.01)

Post 0.29 (0.01)

0.31 (0.01)

0.21 (0.01)

†

P

**

*

**

NS

**

*

0.33 (0.01)

0.25 (0.01)

0.20 (0.01)

0.24 (0.01)

0.19 (0.01)

NSNS

0.03 (0.01)

0.11 (0.01)

0.03 (0.01)

Post 0.02 (0.01)

0.07 (0.01)

0.02 (0.01)

**

NS

†

P

**

**

**

**

**

**

NS

**

−0.12 (0.01) −0.15 (0.01) −0.10 (0.01) **

**

NS

**

**

**

NS

**

**

**

NS

**

*

*

NS

NS

**

R5-R20 (kPa/L/s)
Pre
†

P

NS

X5 (kPa/L/s)
Pre

Post −0.11 (0.01) −0.13 (0.01) −0.09 (0.01)
†

P

NS

NS

NS

Fres (Hz)Pre

11.5 (0.5)

16.7 (0.3)

11.2 (0.3)

Post 10.3 (0.3)

14.6 (0.5)

10.8 (0.3)

**

NS

†

P

*

AX (kPa/L)
Pre

0.32 (0.03)

0.78 (0.08)

0.25 (0.02)

Post 0.24 (0.02)

0.53 (0.07)

0.21 (0.01)

**

**

**

100.6 (2.4)

104.0 (2.0)

105.0 (1.6)

Post 102.8 (2.4)

Spirometry
%FVC
Pre
†

P

107.6 (2.2)

107.1 (1.6)

NS

NS

NS

99.4 (2.2)

101.9 (2.3)

103.1 (1.4)

%FEV1
Pre

Post 103.3 (2.3)
†

P

NS

106.2 (2.5)

106.2 (1.5)

NSNS

81.7 (0.8)

83.5 (0.8)

FEV1/FVC
Pre85.3 (1.2)

Post 86.9 (1.2)†

P

82.1 (0.8)

84.3 (0.7)

NS

NS

NS

80.7 (4.0)

73.0 (3.4)

82.9 (2.5)

%MMEF
Pre

Post 90.2 (4.4)
†

P

NS

Resistless

100.8 (2.3)

105.6 (3.0)

112.4 (1.8)

Post 113.2 (2.4)

NS

Post 0.28 (0.01)

78.8 (3.7)

90.9 (2.9)

NS

*

Pre
†

R20 (kPa/L/s)
Pre

Peripheral‡

P C-P C-R P-R%PEF

R5 (kPa/L/s)
Pre

Post-hoc test

CentralP**

119.8 (3.3)

123.4 (2.7)

**

**

**

NS

**

*

The data are shown as mean (SEM). Differences between the baseline andafter treatment were analyzed by a paired t-test (†P). Differences among
subtypes were tested by nonrepeated ANOVA (‡P) with the Student–Newman–
Keuls test (Post-hoc test). C-P: between central type and peripheral type; C-R:
between central type and resistless type; P-R: between peripheral type andresistless type. *: p < .05, **: p < .01 and NS: not significant

15%, sinobronchial syndrome in 8%, and GERD in 7%[2]. From these reports, it appears that CVA is the mostcommon cause of chronic persistent cough. Moreover,
CVA is a precursor and a variant form of clinical asthma
with typical symptoms of wheezing and dyspnea, unlessadequate ICS treatment is provided [4, 22–24]. Additionally, previous studies have indicated the involvementof eosinophilic inflammation in CVA, as well as inclassic asthma, as mentioned in the Introduction. Thus,
it is especially important to use ICSs for the treatmentof CVA. However, the most effective way to use ICSs in
CVA treatment remains unclear. In this study, we havedetermined that subtype classification by IOS could be
useful for the choice of ICS for treatment.
The values of the spirometry and health status (LCQ
scores) at the baseline did not differ among the CVA
subtypes and the ICS groups (Table 1). However, there
were significant differences among subtypes when the efficacy of ICSs was evaluated by LCQ. Coarse-particle
ICSs (FP) increased LCQ scores in the central type compared with other subtypes. Moreover, fine-particle ICSs
(MF) increased the LCQ scores in the peripheral type(Fig. 2). These results indicate that coarse-particle ICSs
are the most suitable for the central type of CVA andfine-particle ICSs are the most suitable for the peripheral
type of CVA. On the other hand, moderate-particle ICSs
(BUD) appear to be effective for both the central andperipheral types. Considering these results, we conclude
that the differences in phenotypes in the IOS parameters
are possibly related to the effectiveness of ICSs. In otherwords, the IOS examination should be performed forpatients with CVA prior to ICS administration, and it isbetter to use ICS with a coarse-particle size for thecentral type and ICS with a fine-particle size for the
peripheral type.
IOS measurements in persistent bronchial asthma
correlate with clinical symptoms and asthma management [11, 25]. However, few studies on the correlationof IOS with spirometry have been reported [26–28].

Sugawara et al. Respiratory Research(2019) 20:41

Page 7 of 10

Fig. 3 Comparison of impulse oscillometry index at baseline (Pre) and after treatment (Post). The data are expressed as the mean ± SEM.
Differences between pre and post were tested by Wilcoxon signed-rank test. **: p < .01

Thus, it is thought that IOS is limited to being adiagnosis-supporting device. Small airways play an important role in persistent bronchial asthma. Lipworth identified
persistent bronchial asthma with persistent small airway injury and poor control as a small airway asthma phenotype[29]. This is the first report to reveal the correlation
between %PEF in spirometry and IOS parameters in CVA(Fig. 4). We believe that IOS is a useful device for the assessment of diseases located in peripheral airway, including
CVA, because a slight change in such a lesion can bedetected earlier with IOS than with spirometry [12, 30, 31].

Although there are only a few reports on the use of
IOS for chronic persistent cough and CVA, it has beenreported that the value of the baseline IOS did not differ
significantly between patients with CVA and those withclassic asthma, [32] and CVA indicated lower R5-R20,
Fres, and AX, and higher X5 compared with classic
asthma [33]. In addition, the level of R5 and R20
decreased in chronic persistent cough after treatment
with ICSs and LABA, although there were no correlations between airway resistance and exhaled NO [34]. In
addition to these reports, after treatment, R5 and R20

Fig. 4 The relationships between %PEF in spirometry and %R5, %R20, and X5 in IOS. In each case, linear regression lines have been fitted.
Spearman’s test. R2: Spearman rank-correlation coefficientSugawara et al. Respiratory Research(2019) 20:41

Page 8 of 10

Fig. 5 Comparison of IOS index in the ICS therapy groups in the central type and peripheral type at the baseline and after treatment. Bars are
expressed as the mean ± SEM. Refer to Additional file 1: Table S2 for the original data. Differences between the baseline and after treatment were
tested by a paired t-test. *: p < .05, **: p < .01, NS; not significant

decreased in this analysis (Fig. 3). Thus, our observations
appear to be compatible. This report is also the first on
the subtype classification for CVA based on IOS parameters. We have observed that there was no difference incharacteristics and spirometry among the subtypes(Table 1); however, the efficacy of ICS treatment correlated with the ICS particle size (Fig. 2). Thus, we conclude that IOS could be a useful device in the treatmentof CVA.
Whether a correlation exists between the value ofresistance in IOS and the pathological change remains
unclear because of its less scientific basis. Regarding biopsy specimens of central airway mucosa and BAL fluid
recovered from the peripheral airways, some studies
have reported the presence of eosinophilic inflammationin the central and/or peripheral airway in patients withCVA [8]. In addition, structural changes secondary to
airway inflammation have been reported in mucosal

biopsies [35]. A computed tomography study revealed
airway wall thickening in CVA [36]. Hence, we believethat the central airway-type or peripheral-type patientsmight have eosinophilic inflammation in the central or
peripheral airways, respectively.
This study, as well as IOS, has some limitations.
Spirometry is extensively adopted in studies for CVA or
asthma. Being a novel methodology, IOS has not yet
been adopted in many facilities, resulting in fewer evidence of the exact meaning, interpretation, and clinicalapplication of IOS parameters compared with those of
spirometry. As some data suggest that IOS should be
used to evaluate the abnormal distal airway function,even in the standard spirometry setting, we believe that
IOS could potentially detect the impairment of small orlarge airway function. As established normative values indifferent populations and comparability between different devices are lacking in IOS, developing robustSugawara et al. Respiratory Research(2019) 20:41

reference values for IOS is imperative. In patients selection, we excluded chronic persistent cough that are notclearly CVA clinically and patients showing efficacy in
LABA and ICS were diagnosed as CVA retrospectively.
So, it is undeniable that the possibility of other cases ofchronic persistent cough being mixed. In addition, CVA
is common among children; however, children were notincluded in this study. Hence, pediatric cases should also
be examined in the future trial. Although we mentioned
the relationship between the particle size of ICS and IOS
parameters, it is also true that the effectiveness of thethree ICS devices cannot be simply determined by particle size. Also, it was a small, retrospective observational
study. The patients were divided into three subtypes, inaddition to the three types of ICS therapy; thus, thenumber of cases in each group was low. Furthermore,
our follow-up period was short (mean observation
period, 1.4 months). Long-term observations of CVA
subtypes classified by IOS are needed to be able to predict how these phenomena will change over a longer
follow-up.

Conclusions
In conclusion, we have investigated the effect of treatment with ICSs and their relation to the parameters of
IOS in patients with clinical CVA. Thus, phenotypic differences in IOS parameters could be associated with theefficacy of ICSs. Coarse-particle ICSs are effective for patients with central airway resistance, and fine-particle
ICSs are effective for patients with peripheral airway resistance. Hence, we recommend the IOS examination
for patients with CVA before the ICS administration. In
addition, we found some variations in phenotype in thepatients with CVA, such as bronchial asthma, and IOS
could detect this slight change earlier than spirometry inperipheral lesions. Therefore, we have concluded that
IOS can be useful for the selection of ICS for CVA treatment and the evaluation of CVA phenotype.
Additional file
Additional file 1: Table S1. Characteristics and parameters over ICS
group in subtypes. The data were showed as Mean (SEM) or number(Percentage). Definition of abbreviations is same as indicated in Table 1.
Table S2. Comparison of impulse oscillometry and spirometry over ICS
group in subtypes at baseline (Pre) and after treatment (Post). Definitionof abbreviations is same as indicated in Table 1. The data were showed
as Mean (SEM). Differences between baseline and after treatment were
tested by un-paired t test (†P). Differences among IOS devices were
tested by non-repeated ANOVA (‡P). *: p < .05, **: p < .01 and NS: nosignificant. (DOCX 149 kb)
Abbreviations
AX: Area of low-frequency reactance; CVA: Cough variant asthma;
FEV1: Forced Expiratory Volume in one second; Fres: Resonance frequency;
FVC: Forced vital capacity; ICS: Inhaled corticosteroid; IOS: Impulse
oscillometry system; LCQ: Leicester cough questionnaire; MMEF: Maximum

Page 9 of 10

mid-expiratory flow; PEF: Peak expiratory flow; R20: Resistance at 20 Hz;
R5: Resistance at 5 Hz; R5-R20: Resistance at 5–20 Hz; X5: Reactance at 5 Hz
Acknowledgments
The authors would like to thank Enago (http://www.enago.com) for the
English language review.
Funding
Not applicable.
Availability of data and materials
Please contact author for data requests.
Authors’ contributions
HS developed the concept and performed the experiments, analyzed andinterpreted the data, and wrote the manuscript. AS contributed to the data
analysis, interpretation of the data, and manuscript revision. SY, KT, and HT
assisted with the data analysis and interpretation and supervised thestatistical analysis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study was approved by the Sapporo Medical Association ethics board.
Competing interests
The authors declare that they have no competing interest.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
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, Sapporo, Hokkaido 060-8543, Japan.
3
Department of Biochemistry, Sapporo Medical University School of
Medicine, Sapporo 060-8556, Japan.
Received: 12 November 2018 Accepted: 11 February 2019

References
1. Fujimura M, Abo M, Ogawa H, Nishi K, Kibe Y, Hirose T, Nakatsumi Y, Iwasa
K. Importance of atopic cough, cough variant asthma and sinobronchial
syndrome as causes of chronic cough in the Hokuriku area of Japan.
Respirology. 2005;10:201–7.
2. Matsumoto H, Niimi A, Takemura M, Ueda T, Yamaguchi M, Matsuoka H,
Jinnai M, Chin K, Mishima M. Prevalence and clinical manifestations ofgastro-oesophageal reflux-associated chronic cough in the Japanese
population. Cough. 2007;3:1.
3. Kohno S, Ishida T, Uchida Y, Kishimoto H, Sasaki H, Shioya T, Tokuyama K,
Niimi A, Nishi K, Fujimura M, et al. Committee for the Japanese Respiratory
Society Guidelines for Management of Cough. The Japanese Respiratory
Society guidelines for management of cough. Respirology. 2006;11:S135–86.
4. Corrao WM, Braman SS, Irwin RS. Chronic cough as the sole presenting
manifestation of bronchial asthma. N Engl J Med. 1979;300:633–7.
5. Fujimura M, Sakamoto S, Matsuda T. Bronchodilator-resistive cough inatopic patients: bronchial reversibility and hyperresponsiveness. Intern Med.
1992;31:447–52.
6. Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP
evidence-based clinical practice guidelines. Chest. 2006;129:80S–94S.
7. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinicalmanifestations and implications for treatment. Thorax. 2002;57:178–82.
8. Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F. Eosinophilic
inflammation in cough variant asthma. Eur Respir J. 1998;11:1064–9.
9. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition ofhydrofluoroalkane-134a beclomethasone is greater than that ofchlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone : across-over study in healthy volunteers. Chest. 2002;122:510–6.
10. Carvalho TC, Peters JI, Williams RO 3rd. Influence of particle size on regionallung deposition--what evidence is there? Int J Pharm. 2011;406:1–10.

Sugawara et al. Respiratory Research(2019) 20:41

11. Takeda T, Oga T, Niimi A, Matsumoto H, Ito I, Yamaguchi M, Matsuoka H,
Jinnai M, Otsuka K, Oguma T, Nakaji H, Chin K, Mishima M. Relationshipbetween small airway function and health status, dyspnea and disease
control in asthma. Respiration. 2010;80:120–6.
12. Oppenheimer BW, Goldring RM, Herberg ME, Hofer IS, Reyfman PA,
Liautaud S, Rom WN, Reibman J, Berger KI. Distal airway function insymptomatic subjects with normal spirometry following world trade center
dust exposure. Chest. 2007;132:1275–82.
13. Niimi A. Cough and asthma. Curr Respir Med Rev. 2011;7:47–54.
14. Shirai T. Is R5-R20 a marker of small airway function? Respir Investig. 2018;56:199–200.
15. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, Marchal F,
Measurements ERSTFoRI. The forced oscillation technique in clinicalpractice: methodology, recommendations and future developments. Eur
Respir J. 2003;22:1026–41.
16. Smith HJRP, Goldman MD. Forced oscillation technique and impulse
oscillometry. Eur Respir Monogr. 2005;31:72–105.
17. Goldman MD. Clinical application of forced oscillation. Pulm Pharmacol
Ther. 2001;14:341–50.
18. Nieto A, Pamies R, Oliver F, Medina A, Caballero L, Mazon A. Montelukast
improves pulmonary function measured by impulse oscillometry in children
with asthma (Mio study). Respir Med. 2006;100:1180–5.
19. SU VJ. Impulse Oscillometry. Analysis of lung mechanics in general practiceand clinic, epidemiological and experimental research. Frankfurt: PMIVerlagsgruppe; 1994. p. 148–52.
20. Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID.
Development of a symptom specific health status measure for patientswith chronic cough: Leicester cough questionnaire (LCQ). Thorax. 2003;
58:339–43.
21. Niimi A, Ogawa H. The Japanese version of Leicester Cough Questionnaire(LCQ). The 11th Japanese cough conference Abstract (in Japanese). 2009:22.
http://jtd.amegroups.com/article/view/3296/html
22. Koh YY, Jeong JH, Park Y, Kim CK. Development of wheezing in patientswith cough variant asthma during an increase in airway responsiveness. Eur
Respir J. 1999;14:302–8.
23. Fujimura M, Ogawa H, Nishizawa Y, Nishi K. Comparison of atopic coughwith cough variant asthma: is atopic cough a precursor of asthma? Thorax.
2003;58:14–8.
24. Matsumoto H, Niimi A, Takemura M, Ueda T, Tabuena R, Yamaguchi M,
Matsuoka H, Hirai T, Muro S, Ito Y, Mio T, Chin K, Nishiyama H, Mishima M.
Prognosis of cough variant asthma: a retrospective analysis. J Asthma. 2006;
43:131–5.
25. Gonem S, Natarajan S, Desai D, Corkill S, Singapuri A, Bradding P, Gustafsson
P, Costanza R, Kajekar R, Parmar H, Brightling CE, Siddiqui S. Clinicalsignificance of small airway obstruction markers in patients with asthma.
Clin Exp Allergy. 2014;44:499–507.
26. Yamaguchi M, Niimi A, Ueda T, Takemura M, Matsuoka H, Jinnai M, Otsuka
K, Oguma T, Takeda T, Ito I, Matsumoto H, Hirai T, Chin K, Mishima M. Effectof inhaled corticosteroids on small airways in asthma: investigation using
impulse oscillometry. Pulm Pharmacol Ther. 2009;22:326–32.
27. Qi GS, Zhou ZC, Gu WC, Xi F, Wu H, Yang WL, Liu JM. Detection of the
airway obstruction stage in asthma using impulse oscillometry system. J
Asthma. 2013;50:45–51.
28. Williamson PA, Clearie K, Menzies D, Vaidyanathan S, Lipworth BJ.
Assessment of small-airways disease using alveolar nitric oxide and impulse
oscillometry in asthma and COPD. Lung. 2011;189:121–9.
29. Manoharan A, Anderson WJ, Lipworth J, Ibrahim I, Lipworth BJ. Small
airway dysfunction is associated with poorer asthma control. Eur Respir
J. 2014;44:1353–5.
30. Pisi R, Tzani P, Aiello M, Martinelli E, Marangio E, Nicolini G, Olivieri D, Chetta
A. Small airway dysfunction by impulse oscillometry in asthmatic patientswith normal forced expiratory volume in the 1st second values. Allergy
Asthma Proc 2013;34:e14–20.
31. Shi Y, Aledia AS, Tatavoosian AV, Vijayalakshmi S, Galant SP, George SC.
Relating small airways to asthma control by using impulse oscillometry inchildren. J Allergy Clin Immunol. 2012;129:671–8.
32. Yoon JWHH, Jee HM, Baek JH, Kim HY, Shin YH, Han MY. Comparison of
bronchial responsiveness assessing dose-response slope between coughvariant asthma and classic asthma in young children. Allergy Asthma Respir
Dis. 2013;1:309–13.

Page 10 of 10

33. Obase Y, Shimoda T, Kishikawa R, Kohno S, Iwanaga T. Trigger of bronchial
hyperresponsiveness development may not always need eosinophilic
airway inflammation in very early stage of asthma. Allergy Rhinol(Providence). 2016;7:1–7.
34. Nakano C. Utility of MostGraph and fractional exhaled nitric oxide
measurement in chronic cough. J Med Soc Toho. 2014;61:81–91.
35. Niimi A, Torrego A, Nicholson AG, Cosio BG, Oates TB, Chung KF. Nature of
airway inflammation and remodeling in chronic cough. J Allergy Clin
Immunol. 2005;116:565–70.
36. Niimi A, Matsumoto H, Amitani R, Nakano Y, Mishima M, Minakuchi M,
Nishimura K, Itoh H, Izumi T. Airway wall thickness in asthma assessed bycomputed tomography. Relation to clinical indices. Am J Respir Crit CareMed. 2000;162:1518–23.