Allergology International (1997) 46: 51-56

Original Article

Clinical features of Japanese patients with chronic

cough induced by gastroesophageal reflux

Katsuya Fujimori,1 Eiichi Suzuki2 and Masaaki Arakawa21Department of Internal Medicine

, Niigata Prefectural Shibata Hospital, Shibata, and 2Second Department

of Medicine, Niigata University School of Medicine, Niigata, Japan

ABSTRACT

Gastroesophageal reflux (GER) has been reported as a cause of chronic cough (CC) in the United States. It has been reported that 5-21% of CC cases are induced by GER. In Japan, however, detailed clinical features of CC induced by GER have not been described. The

present study reports on six Japanese patients with GER-induced CC. The subjects were all females, with a mean age of 72 years. The average body mass index was 37kg/m2, indicating obesity. No abnormalities were found with regard to concentrations of C-reactive

protein, peripheral eosinophil counts, serum IgE concentrations, serum titers of cold agglutinins or anti-bodies to Mycoplasma pneumoniae, chest radiograph findings, respiratory function tests or blood gas analy-ses. Bronchial biopsy was performed in three patients and showed chronic inflammation characterized by lymphocytic infiltration, squamous metaplasia and mucosal basement membrane thickening. In the study

population (Japanese patients), GER-induced CC tended to occur in elderly obese women and may be attributable to airway inflammation.

Key words: bronchial biopsy, chronic inflammatory

airway disease, cough, gastroesophageal reflux,

Japanese.

INTRODUCTION

Chronic cough (CC) is defined as persistent cough of unknown etiology with a duration of at least 3 weeks.1,2

Postnasal drip syndrome, cough variant asthma3 and

gastroesophageal reflux (GER) have been reported as major causes of this disorder in the United States.1,2 In Japan, however, few cases of CC induced by GER have been reported.4

Body mass index (BMI) and gastric acid pH, which are closely related to the risk of GER,5 differ among the human races.6,7 Thus, differences in factors associated with GER between patients in Japan and those in the United States may affect the incidence of GER-induced cough. We report on the clinical features of Japanese patients with GER-induced CC. In addition, we discuss the etiol-ogy of CC, based on the results of bronchial biopsies

performed using fiberoptic bronchoscopy.

METHODS

Patients

Of patients referred to the Medical Department at Niigata Prefectural Kakizaki Hospital and diagnosed with CC between April 1992 and March 1994, those that met the pre- and post-treatment diagnostic criteria of Irwin et al.1,2 were entered into the study.

The pretreatment criteria were: (i) symptoms of heart-burn and a sour taste in the mouth; (ii) barium reflux dur-ing upper gastrointestinal contrast roentgenography; and

(iii) esophagitis confirmed by esophagoscopic biopsy. The post-treatment criteria were recovery from cough after the following regimen: (i) an anti-reflux diet of high

protein and low fat for three meals a day; (ii) avoiding eating and drinking 2-3h prior to sleep except for taking medications, (iii) elevation of the upper body when lying down; and (iv) administration of metoclopramide and/or H2 receptor antagonists.

Correspondence: Dr Katsuya Fulimori, Department of Internal Medicine, Niigata Prefectural Shibata Hospital, Ohte-cho 4-5-48, Shibata 957, Japan.

Email:k-fuji@ta2.so-net.or.jp Received 28 October 1996. Accepted for publication 24

January 1997.

52 K FUJIMORI ET AL.

Informed consent was obtained from each subject

before the start of the study, which was approved by the

institute's committee on human research.

Clinical findings

The following clinical features were ascertained: age,

sex, smoking history, past allergic history (bronchial asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis), sinus disease history, presence or absence of postnasal drip, BMI (kg/m2), time of cough (morning, afternoon, evening, bedtime, sleep or all day), duration of cough, time between treatment and recovery, levels of C-reactive protein (CRP), peripheral eosinophil counts, serum IgE concentration, serum titers of cold agglutinins and antibodies to Mycoplasma pneumoniae, vital capac-ity (%VC, %predicted values), forced expiratory volume in 1s (FEV1.0%), blood gases (PaO2, A-aDO2), chest roent-

genogram, and esophagoscopic findings, classified according to Savary and Miller.8 Serum IgE concentration and titers of antibodies to M. pneumoniae were mea-sured by enzyme immunoassay and complement fixation, respectively (Biomedical Laboratories Corp., Tokyo,

Table 1. Clinical characteristics of the study groups

Japan). Respiratory function was determined using a hot-wire flowmeter (Autospiro AS-7, Minato Corp., Tokyo, Japan). The %VC was predicted using the equation of Baldwin et al.,9 and FEV1.0% was calculated according to the method of Gaensler.10 Blood gases were analyzed as follows. After having the patient in a supine position for at least 15min, blood was collected from the brachial artery into a heparinized container. PaO2 and PaCO2 were then measured with an automatic pH blood gas analyzer

(Ciba Corning 278, Ciba-Corning-Diagnostic Corp., Tokyo, Japan). The ideal alveolar oxygen tension was cal-culated from PaCO2 according to the method of Comroe et al.," and used to calculate the alveolar-arterial oxy-

gen tension gradient (A-aDO2). Esophagoscopic findings were evaluated by two or more gastroenterologists. In addition, patients underwent bronchial biopsy via flexible bronchoscopy with specimens taken from the segmental bronchi of the upper, middle and lower lobes.

Results are expressed as the mean±standard devia-

tion and range of values.

RESULTS

Forty-three patients were diagnosed with CC during the two years. The 43 cases included 22 cases of post-infectious cough,12, 13 7 of angiotensin-converting enzyme

(ACE) inhibitor-induced cough,14, 15 7 of bronchodilator-resistant cough,16, 17 and 1 of cough variant asthma.3

Six patients met the diagnostic criteria1, 2 for GER-induced CC (Tables 1, 2). None of the patients had used ACE inhibitors. They were all female patients with a meanage of 72±6 years (range, 61-80), and did not have a

history of smoking, allergies or sinus disease. No patient

Table 2. Laboratory findings

CHRONIC COUGH AND GER 53

Fig. 1 Histologic features of bronchial biopsy specimens (case 3) showing (a) chronic inflamma-tion with lymphocytic infiltration in the submucosa (HE) and (b) mucosal basement membrane thickening and focal squamous metaplasia (HE).

had postnasal drip. The mean BMI was 37±2kg/m2

(range, 35-40). As regards the time of cough, all patients indicated that their cough occurred primarily duringsleep. The mean duration of cough was 22±22 weeks

(range, 5-64) and the mean period between treatmentand recovery was 4.3±1.4 weeks (range, 3-6).CRP con-

centrations, peripheral eosinophil counts, serum IgE con-

centrations, and titers of cold agglutinins and antibodies

to M. pneumoniae were all normal.

Mean values for %VC (91.1±8.8%), FEV1.0% (78.8±

7.2%), PaO2 (79.6±4,3 torr) and A-aDO2 (18.6±5.2 torr)

were all within normal range. Chest roentgenograms did

not reveal any abnormalities.

Reflux esophagitis, as detected by esophagoscopy, was

classified according to Savory and Miller's criteria;8 three

patients had stage I esophagitis, 2 had stage II, and 1 had stage IV

Bronchial biopsy was performed in 3 of the 6 cases

before treatment. The results are shown in Figs 1, 2 and

3. All three had lymphocytic infiltration of the bronchial

mucosal membranes, but no abnormal eosinophilic infil-

tration. Bronchial basement membrane thickening was

54 K FUJIMORI ET AL.

Fig. 2 Light microscopy of a bronchial biopsy specimen from case 2 showing an increased degree of lymphocytic infiltration and mucosal basement membrane thickening (HE).

Fig. 3 Light microscopy of a bronchial biopsy specimen from case 4 showing an increased degree of lymphocytic infiltration and submucosal edema (HE).

observed in two cases. One case showed squamous

metaplasia. Thus, these three patients were diagnosed

with chronic airway inflammation accompanied by lym-

phocytic infiltration.

DISCUSSION

In the present study, all six cases of CC induced by GER

occurred in elderly obese women who had neither an

allergic history nor postnasal drip. They showed normal

CRP concentrations, peripheral eosinophil counts, serum IgE concentrations, titers of cold agglutinins and antibod-ies to M. pneumoniae, chest roentgenograms, respiratory function tests and blood gases. In addition, three patients were diagnosed by bronchial biopsy as having chronic airway inflammation accompanied by lymphocytic infil-tration. Irwin et al. reported that 10% of 49 CC cases

were induced by GER, with a mean age of 67 years

(range, 55-77).1 They also reported nine patients with GER having CC as the only symptom,18 consisting of four

CHRONIC COUGH AND GER 55

male and five female patients with a mean age of 52

years. Our six patients were all female and older (mean age of 72 years) than those studied by Irwin et al. It is well known that ACE inhibitors induce cough more frequently in women than in men.15 Moreover, it has been reported that cough is induced more easily in women than in men.19 Therefore, a female predominance of GER-induced CC is compatible with these reports.

Bronchial asthma is considered to be a chronic inflam-matory disease mainly induced by eosinophilic infiltration of the airways.20 In the present study, bronchial biopsy revealed that GER-induced CC may be due to chronic airway inflammation characterized by lymphocytic infil-tration. Boulet et al. performed bronchial biopsies in seven patients with CC induced by GER (all females) as well as in five with CC induced by both GER and post-nasal drip (one male and four females).21 They observed the presence of airway inflammation associated with a lymphocytic infiltration. Furthermore, in their study, 10 of

the 11 cases were female with normal values for FVC and FEV1.0%. These results agree with the findings reported here. With regard to the etiology of GER-induced CC, two hypotheses have been proposed. One is microaspiration of hydrochloric acid into the lung due to GER.22 The other is bronchoconstriction caused by vagal reflexes from the esophagus, trachea and bronchi, enhanced by stimula-tion of esophageal mucosa by hydrochloric acid.23-25 It is difficult to draw definitive conclusions regarding the mechanism underlying our results. However, based on the bronchial biopsy findings, we speculate that repeated tracheobronchial microaspiration of refluxed gastric acid or vagally mediated reflux may cause chronic inflamma-tory damage in bronchial mucosa, in most cases accom-

panied by lymphocytic infiltration, resulting in CC. In Japan, further study is needed to investigate the mecha-nism of reflux-induced cough and airway inflammation, to establish whether the mechanism is that of microaspi-ration or vagally mediated reflux.

ACKNOWLEDGEMENT

The authors thank Dr Yasuharu Saito for helpful com-

ments on the manuscript.

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