389

CASE REPORT
A case of chest tightness variant asthma : the usefulness offractional exhaled nitric oxide as a marker for the diagnosis
and clinical improvement.
Masaki Hanibuchi1, Atsushi Mitsuhashi2, Tatsuya Kajimoto1, Atsuro Saijo1, and Tetsuya Kitagawa3
Department of Respiratory Medicine, 3Department of Cardiovascular Surgery, Shikoku Central Hospital of the Mutual aid Association ofPublic School teachers, Shikoku-Chuo, Japan, 2Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan1

Abstract : A 50-year-old woman was referred to our hospital for further examination of severe constricting painat the right-side dominant anterior chest. She had medical history of outgrown childhood asthma and allergies
to several animals. Chest auscultation revealed no wheezes, rhonchi and other crackles. Laboratory findings
showed an eosinophilia and an elevation of total immunoglobulin E. The results of an electrocardiogram, a chest
X-ray and a chest CT were unremarkable. A fractional exhaled nitric oxide value remarkably elevated, but theabnormalities in pulmonary function test were modest. Her chest pain was ameliorated after inhaling procaterol.
Based on these findings, a diagnosis of chest tightness variant asthma was formulated, and we started treatment
with inhaled corticosteroid / long acting β2 agonist. At two-weeks after treatment, her symptom markedly improved and a fractional exhaled nitric oxide value decreased, which led to a definitive diagnosis of chest tightness variant asthma. A fractional exhaled nitric oxide value further decreased to the normal range in consistent
with symptom disappearance at 10-months after treatment, indicating the usefulness of fractional exhaled nitricoxide as a promising marker for the diagnosis and clinical improvement of chest tightness variant asthma. J.
Med. Invest. 68 : 389-392, August, 2021
Keywords : chest tightness variant asthma, fractional exhaled nitric oxide, biomarker

INTRODUCTION
Asthma is a chronic inflammatory respiratory disease thatis commonly characterized by airway hyperresponsiveness andreversible airway obstruction in the airway, and all asthmatics share common physiologic airway abnormalities in theory.
Despite these shared features, asthma has been recognized tohave the great heterogeneity and may be manifested in various
clinical phenotypes (1, 2). In 2013, Shen et al. reported patientswith atypical asthma whose sole presenting clinical manifestation was chest tightness and referred to this type of asthma as
chest tightness variant asthma (CTVA) (3). CTVA is considered
as a rare variant form of asthma, but sufficient data are yet tobe collected to clarify its accurate disease concept. In the present
report, we demonstrated a case of CTVA who presented chest
pain as the sole symptom and highlighted the usefulness of fractional exhaled nitric oxide (FeNO) as a promising marker for thediagnosis and clinical improvement of CTVA.

CASE REPORT
A 50-year-old woman was referred to our hospital from anearby clinic for further examination of severe constricting painat the right-side dominant anterior chest from three weeks ago.
It was the episode that she had never experienced before, andAbbreviations
CTVA, chest tightness variant asthma ; FeNO, fractional exhalednitric oxide ; IgE, immunoglobulin E ; ppb, parts per billion ; %PEF,・percent predicted peak expiratory flow ; %V50, percent predicted・・・V50 ; %V25, percent predicted V25 ; FEV1, forced expiratory volume
in 1 second ; FVC, forced vital capacity ; %VC, percent predicted vitalcapacity ; ICS, inhaled corticosteroid ; LABA, long acting β2 agonist ; CVA, cough variant asthma

the episodes of severe constricting pain lasted for a few minutes,
which followed by the weak pain of several-hour duration. Whileshe did not have any other complaints, her symptom did not ameliorate by non-steroidal anti-inflammatory drugs. She requiredmaintenance dialysis due to chronic kidney disease from 12years ago and had medical history of outgrown childhood asthma and allergies to several animals. She was a never smoker,
and no significant social or family history was reported.
The physical examinations at the initial admission revealed
body temperature of 36.6℃, blood pressure of 144 / 91 mmHg,
pulse of 80 beats per minute and percutaneous oxygen saturation of 98% on room air. The cardiovascular examination
was unremarkable. There were no wheezes, rhonchi and othercrackles in chest auscultation. No evident pretibial and foot pad
edema were seen. The remainder of the physical examinations
was normal. Hematological findings showed normal white blood
cell count (7400 / μL) with eosinophilia (1088 / μL), and mild anemia. Laboratory findings showed elevated levels of blood urea
nitrogen (45.1 mg / dL), creatinine (8.16 mg / dL), potassium (5.5mEq / L), and N-terminal pro-brain natriuretic peptide (1560
pg / mL) due to chronic renal failure. Serum levels of creatine kinase, creatine kinase-MB, and C-reactive protein were normal.
An elevated level of serum total immunoglobulin E (IgE) was observed (779.0 U / mL). Serum antigen-specific IgEs were not measured. The remainder of laboratory test results is shown in Table
1. The results of an electrocardiogram, a chest X-ray and a chest
Received for publication May 6, 2021 ; accepted July 3, 2021.
Address correspondence and reprint requests to Masaki Hanibuchi,
Department of Respiratory Medicine, Shikoku Central Hospital of the
Mutual Aid Association of Public School teachers, 2233 Kawanoe-cho,
Shikoku-Chuo, 799-0193, Japan and Fax : +81-896-58-3464.

The Journal of Medical Investigation Vol. 68 2021

M. Hanibuchi, et al. Diagnostic utility of FeNO for CTVA390

Table 1. Laboratory data at the first admission
Hematology

Biochemistry

Pulmonary function test

WBC

7,400 /μL

AST

9 IU/LVC

2.71 LNeu

48.8 %ALT

9 IU/L%VC

100.7 %

Lymph

28.4 %ALP

81 U/L

FVC

2.76 L

Mono

7.7 %

LDH

134 IU/L%FVC

107.8 %

Eos

14.7 %

γ-GTP

15 U/LFEV12.14 L

CK261 U/L

Baso

0.4 %

RBC

337×10 /μL

Hb410.9 g/dL

CK-MB

9 IU/LT-bil

0.4 mg/dL

Ht

33.2 %

TP

7.5 g/dL

Plt

21.1×10 /μL

4Alb

3.9 g/dLT-cho

153 mg/dL

Amy

137 IU/L

BUN

FEV1/FVC

77.54 %

%FEV1

98.6 %

PEF

5.61 L%PEF

75.0 %

V50

2.34 L

%V50

70.1 %

V25

0.57 L

45.1 mg/dL%V25

42.2 %

Cre

8.16 mg/dL

FeNO

106 ppbNa

140 mEq/L

K

5.5 mEq/L

Cl

102 mEq/L

CRP

0.26 mg/dL

IgE

779 U/mL

NT-proBNP

1560 pg/mL・・・・IgE, immunoglobulin E ; NT-proBNP, N-terminal pro-brain natriuretic peptide ; VC, vital capacity ; %VC, percent predicted vital capacity ; FVC, forced vital capacity ; %FVC, percent predicted forced vital capacity ; FEV1, forced expiratory volume in 1 second ; %FEV1,percent predicted forced expiratory volume in 1 second ; PEF, peak expiratory flow ; %PEF, percent predicted peak expiratory・・・・flow ; %V50, percent predicted V50 ; %V25, percent predicted V25 ; FeNO, fractional exhaled nitric oxide ; ppb, parts per billion

CT were unremarkable. A value of FeNO remarkably elevated at
106 parts per billion (ppb). In a pulmonary function test, valuesof percent predicted peak expiratory flow (%PEF), percent pre・・・・
dicted V50 (%V50), and percent predicted V25 (%V25) slightly
decreased, while those of forced expiratory volume in 1 second(FEV1), forced vital capacity (FVC), FEV1 / FVC, and percent
predicted vital capacity (%VC) were normal. Airway reversibility
test was not performed following the patient’s wishes. Her chest
pain was ameliorated after inhaling procaterol.
Based on these findings, a diagnosis of CTVA was formulated,
and we started treatment with inhaled corticosteroid (ICS) / longacting β2 agonist (LABA) at the initial visit. At two-weeks
after the treatment initiation, her symptom markedly improved
and a FeNO value decreased at 25 ppb. By the confirmation ofremarkable clinical improvement in response to ICS / LABA, adefinitive diagnosis of CTVA was made. She continues treatment
with ICS / LABA even now and chest pain has completely disappeared. At 10-months after the treatment initiation, a FeNO
value further decreased at 7 ppb (Fig. 1).

Figure 1. Comparison of FeNO values before and after treatment
for CTVA.
FeNO values remarkably decreased at two weeks and 10 months after
the treatment initiation compared with that at the initial admission.
®
FeNO values were measured by NIOX VERO electrochemical analyzer(Aerocrine AB, Solna, Sweden) at a flow rate of 50 mL / seconds andwere expressed as ppb.

DISCUSSION
Asthma is a chronic inflammatory respiratory disease that iscommonly characterized by inflammation, hyperresponsiveness,and reversible obstruction in the airway. By definition, all asthmatics share common physiologic airway abnormalities. Despite
these shared features, the great heterogeneity in the severityof airflow limitation and symptoms has been recognized (1).
Although the typical symptoms of recurrent episodes of wheezes,
dyspnea, chest tightness, and cough, occur simultaneously (4),asthma may be manifested in various clinical phenotypes (2).

An atypical patient with asthma who presented solely with chest
tightness was firstly reported by Farr et al. (5), and this phenotype was called as chest pain variant asthma (6, 7). However,this is not generally appreciated, perhaps because these works
were published 30-40 years ago. In 2013, Shen et al. reported 24
patients with asthma whose sole presenting clinical manifestation was chest tightness and referred to this type of asthma as
CTVA (3). As is the case in patients with classic asthma or coughvariant asthma (CVA) (8, 9), patients with CTVA also presented

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The Journal of Medical Investigation Vol. 68 August 2021
with eosinophilic airway inflammation. Recently, Yan et al. advocated the definition of CTVA. According to their criteria, thediagnosis of CTVA is made based on the chest pain or tightness
being the sole symptom and at least one of the following conditions was met : 1) an increase of > 12% and > 200 mL in FEV1
after inhaling short acting β2 agonist ; 2) airway hyperresponsiveness as evidenced by a positive finding of bronchial provocation test ; 3) a weekly variability in diurnal PEF of greaterthan 10% ; and 4) a marked clinical improvement in response
to β2 agonists, with or without ICS (10). The present case also
revealed chest pain as the sole symptom and had medical historyof outgrown childhood asthma and allergies to several animals
with peripheral blood eosinophilia. Her chest pain was ameliorated after inhaling procaterol and had completely disappearedin response to the treatment with ICS / LABA. Taken together
these findings, we made a definitive diagnosis of CTVA.
The clinical phenotypes of asthma are known to be remarkably
different among patients, and it is not unusual in asthmatics forone or more of main symptoms to be absent. Thus, asthma withatypical clinical features such as chest pain and tightness, may
be misdiagnosed as conditions such as chronic bronchitis, cardiovascular diseases and mental disorders (11). Edmondstone
investigated the frequency and characteristics of chest pain inpatients admitted with acute exacerbation of asthma and foundthat chest pain occurred in 76%. These observations suggested
that chest pain is a common symptom in acute severe asthma(12). As the significance of asthmatic chest pain has a tendency
to be neglected in adults, it is worthwhile reminding physiciansthat chest pain and tightness may be related to asthma rather
than cardiovascular diseases. CTVA is considered as a raredisease, and there are few case reports in Japan (Table 2) (13-17).
But the morbidity of CTVA has possibility to be underestimatedfor abovementioned reasons. For the adequate treatment andsymptom relief of CTVA patients, the accurate diagnosis of theetiology of chest pain and tightness is an important clinicalconcern.
FeNO could be an airway eosinophilic biomarker for the assessment and management of asthma (18, 19). We also demonstrated that FeNO levels were higher in CVA and classic asthma
than those in healthy controls and that FeNO were identified
as an independent factor to discriminate CVA and non-CVA(20). Recently, Yan et al. evaluated the therapeutic response to
standard asthma treatments among 76 patients with CTVA ina 52-week multicenter, prospective study (10). There were no
significant improvements in FeNO after 52 weeks comparedwith the baseline level, while chest tightness was significantly
ameliorated among most patients with CTVA after treatment.
However, subgroup analysis revealed that FeNO at the firstadministration in the responsive group was markedly higher
than that in the non-responsive group, indicating that the disease severity of CTVA was associated with FeNO values. In thepresent case, a FeNO value remarkably elevated at the initialvisit (106 ppb), contrary to modest abnormalities in pulmonary
function test. At 10-months after treatment with ICS / LABA, aFeNO value drastically decreased to the normal range (7 ppb)
in consistent with symptom disappearance. To the best of ourknowledge, this is the first report that FeNO might be one ofpromising candidates as a marker for the diagnosis and clinicalimprovement of CTVA.
In acute exacerbation of asthma, the mechanisms of chest pain
are estimated as follows : The chest hyperinflates during severe
asthma and ventilation occurs at lung volumes approaching
total lung capacity. This increases the work of breathing as therespiratory muscles are required to operate at a mechanical disadvantage, resulting in muscle fatigue and consequent pain (12).
Farr et al. attributed the causation of chest tightness in CTVA
patients to the remarkable air trapping and enlarged lungs
by the severely and marginally obstruction of large and small
airways, respectively (5). However, the pathogenesis of chest
pain and tightness in CTVA patients remains unclear. Since
sufficient data are yet to be collected to clarify whether CTVA
can be defined as an independent clinical phenotype regarding
the prevalence, risk factors, course of disease, clinical features,management, and prognosis, further studies are warranted toestablish the accurate disease concept of CTVA.
In conclusion, we herein reported a case of CTVA who had
chest pain as the sole symptom. A remarkable improvement ofsymptom in response to the treatment with ICS / LABA led toa definitive diagnosis of CTVA. While a FeNO value remarkably elevated at the initial visit, it drastically decreased aftertreatment in consistent with the symptom relief, suggestingthat FeNO might be a promising marker for the diagnosis andclinical improvement of CTVA.

CONFLICT OF INTEREST DISCLOSURE
All authors state that they do not have any financial or otherrelationships for the present study that might lead to a conflictof interest.

Table 2. Case reports of chest tightness variant asthma in Japan.
Ref. No.

First author

Age

GenderDiagnosis

Symptom

Wheezes

History Inhalation ofof asthma bronchodilator

13

Kashiwagi H

51

M

Effect of asthma drugs,
diagnosis of asthma

Chest pain,
cough, dyspnea－＋Effective

14

Sano Y

37

M

Effect of asthma drugs,
methacholine test positive

Chest pain－＋Effective

15

Suko M

24

M

Effect of bronchodilator,
acetylcholine test positive

Chest pain, cough,dyspnea, headache－－Effective

16

Taniguchi H

45

F

Effect of LTRA

Chest pain－＋－－－Effective－＋Effective

17Taniguchi H37

M

Effect of bronchodilator

Chest pain,
headachePresent CaseHanibuchi M

50F

Effect of ICS / LABA,
elevation of FeNO value

Chest pain

LTRA, leukotriene receptor antagonist ; ICS / LABA, inhaled corticosteroid / long acting β2 agonist ; FeNO, fractional exhaled nitric oxide

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M. Hanibuchi, et al. Diagnostic utility of FeNO for CTVAACKNOWLEDGEMENTS
We thank our colleagues at Shikoku Central Hospital of theMutual aid Association of Public School teachers, especiallyHitomi Komoda for technical assistance.

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