Shinshu M ed J, 59 ⑷ :239 〜247, 2011

Usefulness of the Measurement of Fractional Exhaled Nitric Oxide
in Asthmatic Patients:Correlation with Pulmonary Function,
Asthma Control and Health Status
Yoshiaki KITAGUCHI , Keisaku FUJIMOTO , Motoki ONO
Yoshimichi KOMATSU , Takayuki HONDA and Keishi KUBO
1） First Department of Internal Medicine, Shinshu University School of Medicine
2） Departments of Biomedical Laboratory Sciences, Shinshu University School of Health Sciences
3） Undergraduate, School of Medicine, Shinshu University School of Medicine
4） Department of Laboratory Medicine, Shinshu University School of Medicine

Background and objective:This study was conducted to investigate whether or not FeNO correlates withlung function tests, the Asthma Control Test (ACT) for assessing asthma control or the Asthma Health
Questionnaire (AHQ‑33)for evaluating the health status in asthmatics.
Methods:FeNO was compared with the results of spirometry,ACT and AHQ‑33 in 57 non‑smoking patientswith asthma and 17 healthy individuals without pulmonary diseases who had never smoked. Sixteen of 57
asthmatics treated with inhaled corticosteroid (ICS)underwent step‑down therapy if they showed good/total
control or step‑up therapy if they showed poor control, and were evaluated by spirometry, ACT and AHQ‑
33 prior to and more than one month after starting step‑down or step‑up therapy.
Results:FeNO in asthmatics was signiﬁcantly higher than that in the control group.There were no signiﬁcantcorrelations between FeNO and FEV , ACT score or AHQ‑33 scores. However, there were signiﬁcantcorrelations between the changes in FeNO and changes in FEV ,ACT score or AHQ‑33 scores following step‑
down or step‑up therapy.
Conclusion :FeNO is a useful marker not only for the diagnosis of asthma but also for asthma control anddetermining the health status in an individual patient, although it is variable without any correlation withsymptoms and lung function among asthmatics. Shinshu Med J 59 : 239 ―247, 2011
(Received for publication March 3, 2011;accepted in revised form May 10, 2011)
Key words:fractional exhaled nitric oxide, Asthma Control Test, Asthma Health Questionnaire

Introduction

NO (FeNO) may be clinically useful for the detection and management of cytokine ‑mediatedEndogenous nitric oxide (NO) is an important

inﬂammatory lung disorders .The concentration of

signaling molecule and may play a role in the regu-

NO is increased in the exhaled air of asthmatics .

lation of airway function .NO gas is produced by

There is immunocytochemical evidence for induci-

various cells within the lower respiratory tract,

ble NO synthase (iNOS) expression in the airway

including inﬂammatory and epithelial cells, and isepithelium of asthmatics , suggesting that thedetectable in the exhaled air of normal humanincrease in NO may be due to induction of iNOS bysubjects . M easurement of the fractional exhaledcytokines and other inﬂammatory mediators
released in asthmatic airways. FeNO levels

Corresponding author:Keisaku Fujimoto
Departments of Biomedical Laboratory Sciences,Shinshu

decrease following the treatment with the improve-

University School of Health Sciences, 3‑1‑1 Asahi,ment of symptoms and airway obstruction in

Matsumoto‑city, Nagano‑prefecture 390‑8621, Japanpatients with acute asthma . Therefore, the mea-

No. 4, 2011

239

Kitaguchi.Fujimoto.Ono et al.

surement of concentration of FeNO has been sug-

FeNO was evaluated in comparison to the results

gested to be a simple and noninvasive way ofof the Asthma Control Test (ACT) for assessing

monitoring inﬂammation of the respiratory tract

asthma control

with a potential role in the diagnosis of disease .

onnaire (AHQ‑33),which is a health‑related quality

However, FeNO is aﬀected by the treatment forand the Asthma Health Questi-of life questionnaire for asthmatics.All subjects

asthma, especially inhaled corticosteroid (ICS) andcompleted a questionnaire regarding their prior

the type of airway inﬂammation, eosinophilic or

respiratory diagnosis, smoking history and current

neutrophilic airway inﬂammation. Some investiga-

medication use,the ACT and the AHQ‑33,and thentors doubt the usefulness of FeNO as a marker ofunderwent FeNO measurement and spirometry.

asthma control. This study cross ‑sectionally

These evaluations were done between 9 am and 11

examined whether FeNO was correlated witham.

asthma control or airﬂow limitation among asthma

Thirteen of 38 asthmatics on ICS therapy whosepatients who had received daily treatments forasthma control varied from good to total control

asthma including ICS and further examined thewith an ACT score of 21〜25 underwent step‑down

relationship between the changes in FeNO andof their therapy, reducing either LTRA, LABA or

asthma symptoms or airﬂow limitation in individual

theophylline, and three asthmatics whose asthma

asthma patient when the treatment underwent

control was poor with an ACT score below 20

either a step‑down or step‑up longitudinally.

underwent step‑up of their therapy.Spirometry,theMethods
A

Subjects
Fifty‑seven non‑smoking asthmatics were re-measurement of FeNO, the evaluation of ACT and
AHQ‑33 questionnaires were examined before and
1 to 6 months after either the step‑down or step‑up.
C

Pulmonary function tests

cruited from the outpatient clinics of Shinshu Uni-

Spirometry was performed using a pulmonary

versity Hospital from April 2009 to September 2009.

function testing system (Chestac‑55V ; Chest Co.

Asthma was diagnosed based on the clinical history

Ltd., Tokyo, Japan). The pulmonary function tests

and symptoms including reversible airﬂow limita-

were performed by two special technicians accord-tion in accordance with the Global Initiative foring to the ATS criterion. Two or three tests were

Asthma (GINA) guidelines . Thirteen of the 57

repeated to guarantee repeatability.

asthmatic patients had never received any steroid

D

Fractional exhaled Nitric Oxide measurement

therapy, 38 patients were treated with ICS of 400

FeNO measurement was performed with a previ-

ug/day ﬂuticasone propionate, and 6 patients with

ously described technique . FeNO levels weremaintenance 2.5‑20 mg/day oral prednisolone (7.9 ±evaluated using a personal device (NIOX M INO;

2.6 mg/day) added to ICS therapy. In addition, 40

Aerocrine AB ;Smidesvagen, Sweden) for measur-patients were treated with leukotriene receptor

ing FeNO levels with identical mouth ﬂow rate andantagonist (LTRA),13 with long‑acting β‑agonists

pressure settings in each subject.The sensor on the(LABA), and 22 with oral theophylline.

device was changed periodically, in line with theSeventeen non‑smoking controls took part in the

manufacturerʼs guidance.The working of the device

study.None of them had histories of respiratory or

is based on electrochemical analysis,which is in line

cardiovascular diseases or received any long‑termwith published procedures for FeNO measurement.

medications.

The method has been validated by chemilumines-

This study was approved by the Human Ethics

cence technology,with an accuracy of ±5 parts per

Committee of Shinshu University School of Medi-

billion (ppb) in comparison to the personal device

cine.

(NIOX MINO; Aerocrine AB ; Smidesvagen,B

Sweden). Data from the analyzer vs. the portable

Study design
240

Shinshu Med J Vol.59

Usefulness of the measurement of FeNO in asthmatic patientsdevice (NIOX ; Aerocrine AB ; Smidesvagen,G

Statistical Analysis

Sweden) showed a mean disagreement of 0.5 ppb

The values shown in the text and tables are the(SD, 3.8 ppb), with high linearity and accuracy inmeans ± SEM. The variables in the two groups

comparison to reference gases . Two successive

were compared with the use of nonparametricrecordings were made at 2‑min intervals, and the

M ann‑Whitneyʼs U tests. Simple correlations

average of two readings was recorded.All measure-

between variables were examined by calculatingments were made by a single observer who had no

Pearsonʼs product correlation coeﬃcient.All statis-

knowledge of the treatment of individual patients.

tical analyses were performed with the use of aE

Windows‑compatible software package (Stat Flex

Asthma Control Test (ACT) survey
The ACT survey is a patient‑completed question-ver. 5.0, Artech Ltd., Osaka, Japan). A P‑value ofnaire with 5 items assessing asthma symptoms (day-less than 0.05 was considered to be signiﬁcant in alltime and nocturnal),use of rescue medications,and

statistical analyses.

the eﬀect of asthma on daily functioning.Each item

Results

includes 5 response options corresponding to a 5‑
point Likert‑type rating scale. In scoring the ACTFeNO was signiﬁcantly higher in asthmatics thanscore,responses for each of the 5 items are summed

in control subjects (Table 1). There was no

to yield a score ranging from 5 (poor control ofsigniﬁcant correlation between FeNO and percent

asthma) to 25 (complete control of asthma). The

predicted FEV in asthmatics (Fig.1).There was no

details of the development of the ACT have beensigniﬁcant correlation between FeNO and FEV /reported elsewhere .

FVC (r＝−0.14) and no signiﬁcant diﬀerence inFAsthma Health Questionnaire ‑33 ‑Japan

FeNO between asthmatics with and without airway(AHQ‑33)

obstruction (62.7±8.3 vs. 46.6±6.0 ppb). There was

The AHQ‑33, which is a disease‑speciﬁc health‑no signiﬁcant correlation between FeNO and ACT

related quality of life questionnaire that is widelyscore or AHQ‑33 total score (Fig. 2) as well as

used in Japan,was employed to assess health status.

subscale scores of AHQ‑33.On the other hand,there

AHQ‑33 was developed based on international ques-

was a signiﬁcant correlation between ACT score

tionnaires such as the Asthma Quality of Life

and AHQ‑33 total score (r＝−0.67, p＜0.01).

Questionnaire (AQLQ)by translating from the Eng-

The asthmatics were classiﬁed into the threelish language, while taking into account bothsubgroups in accordance with the treatment with noJapanese customs and culture.A higher score on the
AHQ‑33 reﬂects poorer health status with respect
to these 33 items. Muraki et al.

showed that theAHQ‑33 was more sensitive for severity than the
Medical Outcomes Study Short‑Form 36‑Item

Table 1 Comparison of the clinical characteristics,
pulmonay function tests and the fractional
exhaled nitric oxide (FeNO) of control subjects and asthmatics
Control

Asthma175753.1±4.1

54.4±2.1

4/13

26/31

%VC, %

110.8±5.4

95.4±4.3%FEV , %108.4±4.7

79.6±4.3

FEV /FVC, %82.2±1.6

70.0±2.1

FeNO, ppb

23.7±2.4

53.9 ±6.9

Health Survey (SF‑36)which was widely used as a
generic health‑related quality of life questionnaire,

Number of patients, n

and that a logistic regression analysis revealed that

Age, yrs old

asthmatic symptoms,factors which worsened symp-

Sex, female/male, n/ntoms, emotion, daily activity, and social activity
subscale scores,as well as a high total 32 item score,on the AHQ‑33 were associated with an increased
risk of moderate to severe asthma. The details of
the development of the AHQ‑33 have been reported
elsewhere .
No. 4, 2011

Values are the mean±SEM.

p＜0.01 vs. Control
241

Kitaguchi.Fujimoto.Ono et al.

Fig. 1 Correlation between the fractional exhaled nitric oxide (FeNO) and percent
predicted FEV in asthmatics (n＝57)

Fig. 2 Correlation between the fractional exhaled nitric oxide (FeNO)and the Asthma Control
Test (ACT)or the Asthma Health Questionnare‑33(AHQ‑33)in asthmatic patients (n＝57)

corticosteroids (steroid‑naı
ve group), ICS (ICS

there were no signiﬁcant diﬀerences among thesegroup), and oral corticosteroid ＋ ICS (OS group).

groups. There were no signiﬁcant correlations

FeNO was signiﬁcantly higher in steroid‑naı
ve

between FeNO and the percent predicted FEV

asthmatics (83.7±15.9 ppb) and asthmatics treated(r＝−0.33), ACT score (r＝0.12) or AHQ‑33 total

with ICS (43.4±7.3 ppb) than in control subjects

score (r＝0.28) as well as the subscale scores of(23.7±2.4 ppb),and the FeNO in steroid‑naı
ve asth-

AHQ‑33 in steroid‑naı
ve asthmatics.

matics was signiﬁcantly higher than that in asth-

Changes in FeNO were compared with changes inmatics in the ICS group (Fig. 3). The FeNO inpulmonary function tests,ACT and AHQ‑33 scores

asthmatics treated with oral corticosteroid (55.9 ±of 16 asthmatics who underwent step‑down or step‑

25.5 ppb) tended to be lower than in steroid‑naı
ve

up of their therapy(Table 2).The concentrations ofasthmatics and higher than in control subjects, but

FeNO were increased in 10 of the 13 asthmatics that242

Shinshu Med J Vol.59

Usefulness of the measurement of FeNO in asthmatic patients

Fig. 3 The fractional exhaled nitric oxide (FeNO)in control subjects (○,n＝17),steroid‑naive
asthmatics (△, n＝13), asthmatics treated with inhaled corticosteroid (□, n＝38) andasthmatics treated with maintenance oral steroids (◇, n＝6)
● (Control), ▲ (Asthma ICS (−)), ■ (Asthma ICS (＋))and ◆ (Asthma OS (＋));mean±
SEM. p＜0.05 and p＜0.01 vs. Control, p＜0.05 vs. Asthma ICS (＋)

underwent step‑down,and all three asthmatics thattions between changes in FeNO and changes inunderwent step‑up showed decreases in their FeNO.

FEV ,ACT score or AHQ‑33 total scores as well as

There was a signiﬁcant correlation between the

4 subscale scores in asthmatics who underwent

changes in FeNO and the changes in FEV (r＝−0.

step‑down or step‑up of their therapy without any

66,p＜0.01),ACT score (r＝−0.56)or AHQ‑33 totalchanges of the ICS dose.

scores (r＝0.77, p＜0.01) as well as the 4 subscalescores (Fig. 4).

FeNO increases in association with eosinophilic
airway inﬂammation measured in BAL, airway

Discussion
FeNO was signiﬁcantly higher in asthmatics.

tissue and induced sputum in asthmatics anddecreases following treatment with ICS .FeNO isa reliable surrogate marker of eosinophilic airway

There were no signiﬁcant correlations between

inﬂammation

FeNO and the percent predicted FEV , ACT score

portable device (NIOX MINO; Aerocrine AB ;for assessing asthma control or any of the AHQ‑33

Smidesvagen, Sweden) is a feasible method to

subscale scores for evaluating health status. There

monitor airway inﬂammation in asthmatics

was no signiﬁcant diﬀerence in FeNO between

However,FeNO is directly aﬀected by the adminis-

asthmatics with and without airway obstruction.

tration of ICS even at lower doses and shows lower

FeNO was signiﬁcantly higher in steroid‑naı
velevels in symptomatic asthmatics treated with ICS

asthmatics than in asthmatics on ICS therapy.

than in steroid‑naı
ve asthmatics since corticoster-

There were no signiﬁcant correlations even between

oids inhibit iNOS in the airway

FeNO and percent predicted FEV , ACT score ortional observation in this studyshowed there was no

any of the AHQ‑33 subscale scores in steroid‑naıvesigniﬁcant correlation between FeNO and percent

asthmatics.However,there were signiﬁcant correla-predicted FEV , ACT score or any of the AHQ‑33

No. 4, 2011

.Daily monitoring of FeNO bythe.

. A cross‑sec-

243

Kitaguchi.Fujimoto.Ono et al.
Table 2 Changes in FeNO and FEV in thirteen asthmatics (No. 1‑13) that underwent step‑down and threeasthmatics (No. 14‑16)that underwent step‑up among 38 asthmatics on ICS therapy
Patient Step‑down or step‑up
number Before

After

Observation ΔFeNO
period (days)
(ppb)

ΔFEV
(ml)

ΔACT ΔAHQ‑33(scores) (scores)

1

ICS＋LABA＋LT＋Th

ICS＋LABA＋Th

120

＋37.5

＋20

0

＋0.41

2

ICS＋LABA＋LT

ICS＋LABA

106

＋22.0

＋60

0

−0.19

3

ICS＋LABA＋LT＋Th

ICS＋LABA＋LT

133

＋20.5

＋280

−1

＋0.19

4

ICS＋LABA＋LT＋Th

ICS＋LABA＋Th

118

＋17.5

＋20

＋4

−0.47

5

ICS＋LABA＋LT＋Th

ICS＋LABA＋Th

46

＋19.5

−120

−4

＋0.19

6

ICS＋LABA＋LT＋Th

ICS＋LABA＋Th

121

＋21.5

−100

0

0.00

7

ICS＋LABA＋LT

ICS＋LT

182

＋57.5

−380

−4

＋0.47

8

ICS＋LABA＋LT

ICS＋LT

170

0.0

＋50

＋1

−0.09

9

ICS＋LABA＋LT

ICS＋LT

85

＋5.5

0

＋1

−0.16

10

ICS＋LABA＋LT

ICS＋LT

85

＋8.0

−90

−3

0.00

11

ICS＋LABA＋LT＋Th

ICS＋LT＋Th

112

−6.5

＋150

0

−0.13

12

ICS＋LABA＋LT＋Th

ICS＋LT＋Th

86

＋78.0

＋20

−3

−0.13

13

ICS＋LABA＋LT

ICS＋LABA

166

−2.0

−120

−1

−0.28

14

ICS＋LABAICS＋LABA＋LT

30

−35.5

＋440

＋18

−1.72

15

ICS＋LT

ICS＋LT＋LABA＋Th

127

−47.5

＋30

＋2

−0.53

16

ICS

ICS＋LABA＋LT＋Th

136−210.0

＋470

＋8

−1.63

113.9
±10.4

−0.9
±15.9

45.6
±53.3

1.1
±1.4

−0.25
±0.15

M ean
±SEM

ICS ;inhaled corticosteroid (ﬂuticasone propionate 400 ug/day), LABA ;long‑acting β‑agonist (salmeterol xinafoate
100 ug/day), LTRA :leukotriene receptor antagonist (montelukast sodium 10 mg/day or pranlukast hydrate 450 mg/day), Th ;theophylline (400 mg/day)
ΔFeNO,ΔFEV ,ΔACT and ΔAHQ‑33;changes in FeNO,FEV ,ACT and AHQ‑33 between the days before and after
step‑down or step‑up

subscale scores in all asthmatics and even interistic in asthma. However, some persistent asth-steroid‑naı
ve asthmatic patients, respectively,sug-

matics also demonstrate neutrophilic airway

gesting that FeNO is variable without any correla-inﬂammation withouttion with symptoms and lung function among asth-inﬂammation , and some patients show increases

matics.

in not only eosinophilic airway inﬂammation but

eosinophilic airway

There is the possibility that subject‑related fac-also neutrophilic airway inﬂammation during exac-

tors inﬂuenced these results. FeNO may beerbation of asthma .According to previous cross‑inﬂuenced by several subject‑related factors othersectional studies, FeNO is correlated with percent

than eosinophilic inﬂammation such as age, genderpredicted FEV in asthmatics .On the other hand,and medications including oral/inhaled corticoster-

Stirling et al.reported that FeNO was not correlat-

oids, beta‑agonists and LTRA . FeNO may not

ed with percent predicted FEV

accuratelyreﬂect airwayinﬂammation in ICS‑treat-patients in this study had a long history of asthma

ed patients. The other reason may be due to(more than 5 years),and some patients showed ﬁxed

heterogeneity of airway inﬂammation in asth-

airﬂow obstruction. The airway remodeling may

matics.Eosinophilic airway inﬂammation is charac-

have aﬀected the results in this study.

244. Most of theShinshu Med J Vol.59

Usefulness of the measurement of FeNO in asthmatic patients

Fig. 4 Correlation between the changes
in the fractional exhaled nitricoxide (FeNO) and changes in
FEV ,changes in the Asthma Control Test (ACT) score or changes
in the Asthma Health Questionnare‑33 (AHQ‑33) in thirteen asthmatics that underwent step‑down
and three asthmatics that underwent step‑up among 38 asthmatics
on ICS therapy (n＝16)

The novel ﬁnding in this study is that there was a

ted that monitoring FeNO and sputum eosinophils

signiﬁcant correlation between changes in FeNO

may be useful in the assessment of airway

and changes in percent predicted FEV ,ACT scoreinﬂammatory changes following ICS therapy inor AHQ‑33 total scores as well as 4 subscale scores

asthmatics . Massaro et al. reported that FeNO

in asthmatics who received step‑down or step‑up

levels were decreased accompanying improvement

therapy with LABA,LTRA or theophylline without

in airway obstruction in patients with acute asthma

any changes of ICS dose.This ﬁnding suggests thatduring their course of treatment with corticoster-

FeNO is a useful marker for asthma control andoids ,suggesting that FeNO may prove useful as an

determining health status during the course of treat-index of asthma severity and treatment eﬃcacy forment.In the previous studies,Jatakanon et al.repor-

an individual patient. The current study found thatNo. 4, 2011

245

Kitaguchi.Fujimoto.Ono et al.

FeNO was increased in parallel with the exacerbat-

status in individual patients, although it is variable

ed symptoms and deterioration of pulmonary func-

without any correlation with the symptoms andtion following step‑down by reducing either LABA,

lung function among asthmatics.

LTRA or theophylline while continuing ICS. These

Acknowledgements

ﬁndings may suggest that FeNO is useful marker
for asthma control under treatment with ICS.

We thank Dr. Hiroko Arioka (Department of

In conclusion, FeNO is considered to be a useful

Respiratory Medicine,International Medical Center

marker not only for the diagnosis of asthma, but

of Japan)for providing the Asthma Health Questi-also for asthma control and determining the healthonnaire‑33‑Japan.

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（2011. 3. 3 received ; 2011. 5.10 accepted）

No. 4, 2011247