A 50-year-old woman was referred to our hospital for further examination of severe constricting pain at 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 the abnormalities 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 nitric oxide as a promising marker for the diagnosis and clinical improvement of chest tightness variant asthma

Hanibuchi, Masaki

Kajimoto, Tatsuya

Kitagawa, Tetsuya

Mitsuhashi, Atsushi

Saijo, Atsuro

English

Tokushima University Institutional Repository

389CASE REPORTA case of chest tightness variant asthma : the usefulness of  fractional exhaled nitric oxide as a marker for the diagnosis and clinical improvement.Masaki Hanibuchi1, Atsushi Mitsuhashi2, Tatsuya Kajimoto1, Atsuro Saijo1, and Tetsuya Kitagawa31Department of Respiratory Medicine, 3Department of Cardiovascular Surgery, Shikoku Central Hospital of the Mutual aid Association of Public School teachers, Shikoku-Chuo, Japan, 2Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sci-ences, Tokushima University, Tokushima, JapanAbstract : A 50-year-old woman was referred to our hospital for further examination of severe constricting pain at 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 the abnormalities 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 im-proved and a fractional exhaled nitric oxide value decreased, which led to a definitive diagnosis of chest tight-ness 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 nitric oxide as a promising marker for the diagnosis and clinical improvement of chest tightness variant asthma. J. Med. Invest. 68 : 389-392, August, 2021Keywords : chest tightness variant asthma, fractional exhaled nitric oxide, biomarkerINTRODUCTION Asthma is a chronic inflammatory respiratory disease that is commonly characterized by airway hyperresponsiveness and reversible airway obstruction in the airway, and all asthmat-ics share common physiologic airway abnormalities in theory. Despite these shared features, asthma has been recognized to have the great heterogeneity and may be manifested in various clinical phenotypes (1, 2). In 2013, Shen et al. reported patients with atypical asthma whose sole presenting clinical manifesta-tion 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 to be 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 frac-tional exhaled nitric oxide (FeNO) as a promising marker for the diagnosis and clinical improvement of CTVA. CASE REPORTA 50-year-old woman was referred to our hospital from a nearby clinic for further examination of severe constricting pain at the right-side dominant anterior chest from three weeks ago. It was the episode that she had never experienced before, and the episodes of severe constricting pain lasted for a few minutes, which followed by the weak pain of several-hour duration. While she did not have any other complaints, her symptom did not ame-liorate by non-steroidal anti-inflammatory drugs. She required maintenance dialysis due to chronic kidney disease from 12 years ago and had medical history of outgrown childhood asth-ma 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 satu-ration of 98% on room air. The cardiovascular examination was unremarkable. There were no wheezes, rhonchi and other crackles 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 ane-mia. Laboratory findings showed elevated levels of blood urea nitrogen (45.1 mg / dL), creatinine (8.16 mg / dL), potassium (5.5 mEq / L), and N-terminal pro-brain natriuretic peptide (1560 pg / mL) due to chronic renal failure. Serum levels of creatine ki-nase, creatine kinase-MB, and C-reactive protein were normal. An elevated level of serum total immunoglobulin E (IgE) was ob-served (779.0 U / mL). Serum antigen-specific IgEs were not mea-sured. The remainder of laboratory test results is shown in Table 1. The results of an electrocardiogram, a chest X-ray and a chest The Journal of Medical Investigation    Vol. 68  2021AbbreviationsCTVA, chest tightness variant asthma ; FeNO, fractional exhaled nitric 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 vital capacity ; ICS, inhaled corticosteroid ; LABA, long acting β2 ago-nist ; CVA, cough variant asthmaReceived 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.　　　　　　　　　　　　　　　　　　　　　　・・　　　・　　　　　　　　　　　・390 M. Hanibuchi, et al.  Diagnostic utility of FeNO for CTVACT were unremarkable. A value of FeNO remarkably elevated at 106 parts per billion (ppb). In a pulmonary function test, values of 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) / long acting 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 of remarkable clinical improvement in response to ICS / LABA, a definitive diagnosis of CTVA was made. She continues treatment with ICS / LABA even now and chest pain has completely dis-appeared. At 10-months after the treatment initiation, a FeNO value further decreased at 7 ppb (Fig. 1). DISCUSSIONAsthma is a chronic inflammatory respiratory disease that is commonly characterized by inflammation, hyperresponsiveness, and reversible obstruction in the airway. By definition, all asth-matics share common physiologic airway abnormalities. Despite these shared features, the great heterogeneity in the severity of 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 pheno-type 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 manifesta-tion was chest tightness and referred to this type of asthma as CTVA (3). As is the case in patients with classic asthma or cough variant asthma (CVA) (8, 9), patients with CTVA also presented Table 1.　Laboratory data at the first admissionHematology Biochemistry Pulmonary function testWBC 7,400 /μL AST 9 IU/L VC 2.71 L  Neu   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/L FEV1 2.14 L  Baso 0.4 % CK 261 U/L FEV1/FVC 77.54 %RBC 337×104 /μL CK-MB 9 IU/L %FEV1 98.6 %Hb 10.9 g/dL T-bil 0.4 mg/dL PEF 5.61 LHt  33.2 % TP 7.5 g/dL %PEF 75.0 %Plt 21.1×104 /μL Alb 3.9 g/dL V50 2.34 LT-cho 153 mg/dL %V50 70.1 %Amy 137 IU/L V25 0.57 LBUN 45.1 mg/dL %V25 42.2 %Cre 8.16 mg/dL FeNO 106 ppbNa 140 mEq/LK 5.5 mEq/LCl 102 mEq/LCRP 0.26 mg/dLIgE 779 U/mLNT-proBNP 1560 pg/mLIgE, immunoglobulin E ; NT-proBNP, N-terminal pro-brain natriuretic peptide ; VC, vital capacity ; %VC, percent predicted vital capac-ity ; 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 billionFigure 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 and were expressed as ppb.・　　　・　　　　　　　　　　　　　　・　　　・・   ・・   ・   ・                                    ・           ・                                    ・391The Journal of Medical Investigation   Vol. 68  August  2021with eosinophilic airway inflammation. Recently, Yan et al. ad-vocated the definition of CTVA. According to their criteria, the diagnosis of CTVA is made based on the chest pain or tightness being the sole symptom and at least one of the following condi-tions was met : 1) an increase of > 12% and > 200 mL in FEV1 after inhaling short acting β2 agonist ; 2) airway hyperrespon-siveness as evidenced by a positive finding of bronchial provo-cation test ; 3) a weekly variability in diurnal PEF of greater than 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 history of outgrown childhood asthma and allergies to several animals with peripheral blood eosinophilia. Her chest pain was amelio-rated after inhaling procaterol and had completely disappeared in 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 for one or more of main symptoms to be absent. Thus, asthma with atypical clinical features such as chest pain and tightness, may be misdiagnosed as conditions such as chronic bronchitis, car-diovascular diseases and mental disorders (11). Edmondstone investigated the frequency and characteristics of chest pain in patients admitted with acute exacerbation of asthma and found that 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 physicians that chest pain and tightness may be related to asthma rather than cardiovascular diseases. CTVA is considered as a rare disease, and there are few case reports in Japan (Table 2) (13-17). But the morbidity of CTVA has possibility to be underestimated for abovementioned reasons. For the adequate treatment and symptom relief of CTVA patients, the accurate diagnosis of the etiology of chest pain and tightness is an important clinical concern.FeNO could be an airway eosinophilic biomarker for the as-sessment and management of asthma (18, 19). We also demon-strated 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 in a 52-week multicenter, prospective study (10). There were no significant improvements in FeNO after 52 weeks compared with the baseline level, while chest tightness was significantly ameliorated among most patients with CTVA after treatment. However, subgroup analysis revealed that FeNO at the first administration in the responsive group was markedly higher than that in the non-responsive group, indicating that the dis-ease severity of CTVA was associated with FeNO values. In the present case, a FeNO value remarkably elevated at the initial visit (106 ppb), contrary to modest abnormalities in pulmonary function test. At 10-months after treatment with ICS / LABA, a FeNO value drastically decreased to the normal range (7 ppb) in consistent with symptom disappearance. To the best of our knowledge, this is the first report that FeNO might be one of promising candidates as a marker for the diagnosis and clinical improvement 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 the respiratory muscles are required to operate at a mechanical dis-advantage, 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 to establish 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 of symptom in response to the treatment with ICS / LABA led to a definitive diagnosis of CTVA. While a FeNO value remark-ably elevated at the initial visit, it drastically decreased after treatment in consistent with the symptom relief, suggesting that FeNO might be a promising marker for the diagnosis and clinical improvement of CTVA.CONFLICT OF INTEREST DISCLOSUREAll authors state that they do not have any financial or other relationships for the present study that might lead to a conflict of interest. Table 2.　Case reports of chest tightness variant asthma in Japan.Ref. No. First author Age Gender Diagnosis Symptom Wheezes History of asthmaInhalation of bronchodilator13 Kashiwagi H 51 M Effect of asthma drugs, diagnosis of asthmaChest pain, cough, dyspnea － ＋ Effective14 Sano Y 37 M Effect of asthma drugs, methacholine test positive Chest pain － ＋ Effective15 Suko M 24 M Effect of bronchodilator,acetylcholine test positiveChest pain, cough, dyspnea, headache － － Effective16 Taniguchi H 45 F Effect of LTRA Chest pain － ＋ －17 Taniguchi H 37 M Effect of bronchodilator Chest pain, headache － － EffectivePresent Case Hanibuchi M 50 F Effect of ICS / LABA, elevation of FeNO value Chest pain － ＋ EffectiveLTRA, leukotriene receptor antagonist ; ICS / LABA, inhaled corticosteroid / long acting β2 agonist ; FeNO, fractional exhaled nitric oxide392 M. Hanibuchi, et al.  Diagnostic utility of FeNO for CTVAACKNOWLEDGEMENTSWe thank our colleagues at Shikoku Central Hospital of the Mutual aid Association of Public School teachers, especially Hitomi Komoda for technical assistance. REFERENCES1. Bhakta NR, Woodruff PG : Human asthma pheno-types : from the clinic, to cytokines, and back again. Immu-nol Rev 242 : 220-232, 20112. Irwin RS : Chest tightness variant asthma (CTVA) : recon-firmed and not generally appreciated. J Thorac Dis 6 : 405-406, 20143. Shen H, Hua W, Wang P, Li W : A new phenotype of asth-ma : chest tightness as the sole presenting manifestation. Ann Allergy Asthma Immunol 111 : 226-227, 20134. The Global Strategy for Asthma Management and Preven-tion, Global Initiative for Asthma (GINA) 2012. Available online : https://www.ginasthma.org/5. Farr RS, Kopetzky MT, Spector SL, Hurewitz DS : Asthma without wheezing. Chest 63 (Suppl) : 64S-68S, 19736. 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Diagnostic utility of FeNO for CTVA

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Diagnostic utility of FeNO for CTVA

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