(Acta Paediatr Jpn 1992; 34: 44 1

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446)

Methacholine Inhalation Challenge in Children with Idiopathic Chest Pain Nobuo Izumi, M.D., Noriyuki Haneda, M.D. and Chuzo Mori, M.D. Department of Pediatrics, Shimane Medical University, Izumo, Shimane, Japan

Bronchial reactivity to inhaled methacholine (MCH) was evaluated in 32 patients with ‘idiopathic’ chest pain. Each pain was recurrent in nature. The incidence of cases with a provocative concentration causing a 20% fall in the forced expiratory volume in 1 sec (PC,,) of 10 mg/ml or less was 62.5%(20 cases), while it was only 11.1%(three cases) in 27 healthy controls. Seventeen patients had no personal history of allergic diseases, elevated serum 1gE level or positive house dust mite-specific IgE antibody. Among these 17, eight (47.1%)had a PC2@of 10 mg/ml or less, the incidence of which was also higher than that of the healthy controls. During the challenge, eight patients complained of chest pain similar to that experienced before. The present results indicate that bronchial hyper-reactivity is an important cause of ‘idiopathic’ chest pain. Patients with unexplained chest pain should be considered for inhalation challenge. Key Words Bronchial hyper-reactivity, Idiopathic chest pain, Methacholine challenge, Recurrent chest pain

Introduction Chest pain is relatively common in pediatric practice. Although it is usually a benign, selflimited symptom, it often causes anxiety to patients and their parents [l-51. While pediatricians should not overlook a rare cardiac disease, they should also explain the etiology and provide reassurance to most patients. But information concerning etiologies and the evaluation and management of chest pain in children is limited. Leading etiologies in previous reports include idiopathic or unexplainable chest pain,

Received December 4, 199 1 Revised March 6, 1992 Accepted March 13, 1992 Correspondence address: Nobuo Izumi, M.D., Department of Pediatrics, Shimane Medical University, 89-1, Enya-cho, Izumo, Shimane 693, Japan.

together with musculoskeletal problems and hyperventilation [ 1-41. Bronchial hyper-reactivity to inhaled metacholine (MCH) has been detected in several patients with unexplained chest pain [6, 71. A relatively high incidence of exercise-induced asthma (EIA) in pediatric patients with chest pain upon exertion has been reported [8], yet apart from the knowledge that bronchial hyperreactivity can cause chest pain it remains poorly recognized. The purpose of this study was to evaluate, by means of MCH inhalation challenge, the clinical significance of bronchial hyper-reactivity in patients with ‘idiopathic’ chest pain.

Patients and Methods Between 1984 and 1989, 32 patients with idiopathic chest pain were studied with MCH. They

442 ( 5 8 ) Izurni et al.

consisted of 21 boys and 11 girls ranging in age from 8 to 16 years (mean 11.4 f 2.3 years). They came to the pediatric clinic of Shimane Medical University Hospital with a chief complaint of chest pain and were diagnosed as having idiopathic chest pain by conventional examinations detailed below. Complete history taking and physical examination were performed with particular attention to hyperventilation, emotional stress and tenderness of the chest wall. A chest X-ray, electrocardiogram (ECG), complete blood cell count, C-reactive protein, serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, creatinine phosphokinase and urinalysis were performed at the initial visit. Patients were then referred to the cardiologist, who examined exercise ECG tests and M-mode as well as 2-D echocardiograms. A Holter ECG monitoring was also performed if necessary. Three patients were excluded because they were too young to perform a pulmonary function test adequately. Study patients had neither a history of upper respiratory tract infection within 6 weeks before MCH challenge nor a history of cigarette smoking. None of them was taking any medication. Informed consent was obtained from the patients and their parents before they were studied.

Characteristicsof pain Of the 32 patients included in this study, 13 experienced pain only during or soon after exercise (Group 1) eight experienced pain only at rest (Group 2), and the remaining 11 experienced pain in both situations (Group 3). Other characteristics of pain at the first visit are summarized in Table 1. All of the pain proved to be recurrent in nature after a 6-12 month followup. Duration was relatively short (i.e. 81% of pain disappeared within 15 rnin). None of the patients complained of wheezing or coughing simultaneously with pain. None appeared to be seriously ill or were awakened by pain at night.

MCH inhalation challenge Baseline spirometry was performed at the beginning of the challenge using a computerized spirometer (Autospirometer AS 2000, Minato

Table 1. Clinical characteristics of chest pain at the first visit for each group Number of patients Group 1 Group 2 Group 3 ( n = 13) (n=8) ( n = 11) Persistence < 1 month 1-6 months > 6 months Frequency Daily 2-6lweek l-7/month Loction Left precordium Sternal Right precordium Indefinite Duration 1-5 min 6-1 5 min 16-60 rnin Description Sharp Dull or oppressive Indefinite

0 3

8 3 3 5

4

4 3 0 4

8 4 1

3 1 4

6 4 I

2 9 2

0 7

5 4 2

1

2 I

1

Medical Science Corp., Osaka, Japan) and the highest forced expiratory volume in 1 sec (FEV,) from three acceptable forced expiratory manoeuvre was used for analysis. Each patient underwent MCH challenge according to a method modified from a previous study [9]. Aerosol was generated by a glass nebulizer (Nissho type, Nippon-shoji Corp., Osaka, Japan) driven with constant air flow of 5 I/min by an air compressor and inhaled by tidal breathing for 2 min with subjects wearing nose-clips. Normal saline was inhaled first, and was followed at 5 min intervals by doubling the concentration of MCH chloride in normal saline. The following six increments of dilution were used: 0.78, 1.56, 3.13,6.25, 12.5 and 25.0 mg/ml. Each nebulizer contained 2 ml solution. The response was measured by FEV, at 0.5 and 1.5 min after each inhalation, and the higher FEV, at each level was used for dose-response analyses. The per cent decline in FEV, after each inhalation was calculated as follows: Baseline FEVl - Postinhalation FEV, Baseline FEV,

x

100

Results were expressed as PC,,, which was obtained from the log dose-response curve by

Acta Paediatr Jpn

Methacholine challengefor chest pain (59) 443 linear interpolation of the point above and below the 20% fall in FEV,. The challenge was terminated prior to completing the dose schedule if FEV, fell by 30% or greater. The results of the MCH challenge were compared with those of 27 healthy controls (13 boys and 14 girls). The controls had no history of allergic diseases, elevated IgE level or positive house dust mite (Dermatophagoides pteronyssinus)-specificIgE antibody. Their age range was between 9 and 16 years old (12.2 k 1.7 years). There was no significant difference in the mean age of patients and controls. Patients were evaluated for personal and family histories of allergic diseases, circulating eosinophil counts, total serum IgE levels by the paper radioimmunosorbent test (PRIST) and house dust mite-specific IgE antibody by the radioallergosolbent test (RAST). More than 250 cells/mm3 peripheral eosinophils and IgE levels higher than 200 IU/ml were considered elevated. Mite-specific IgE antibody levels of 2-4 RAST scores were assessed as positive. Data were analysed using the unpaired Student’s t-test or x2 analysis with Yates’ correction.

Results The results of the MCH challenge in the 27 healthy controls were as follows: eighteen (66.7%) did not have a fall in FEV, of 20% or more; 6 reacted with an FEV, decrease of 20% or more, but had a PC20of more than 10 mg/ml

of, MCH (20.5, 18.0, 14.0, 13.0, 13.0 and 10.5 mg/ml); and three (1 1.1%) had a PC2, less than 10 mg/ml (7.8, 4.0 and 3.4 mg/ml, respectively). A PC20 of less than 10 rng/ml was then defined as increased bronchial reactivity (IBR), and greater than 10 mg/ml was considered normal bronchial reactivity (NBR) in this study. MCH inhalation provoked no chest pain similar to that experienced by the patients. Clinical data are presented in Tables 2, 3 and 4 for groups 1, 2, and 3, respectively. The incidences of patients with IBR were 8/13, 518, and 711 1 for each group, respectively, and there was no significant difference between the groups. Altogether, the incidence of IBR was significantly higher in the patients than in the healthy controls (62.5% vs 11.1%; P < 0.005). During the challenge, chest pain was provoked in eight patients who were all promptly relieved by inhaling bronchodilators. Each of these patients commented that the provoked pain was similar to that previously experienced. As shown in Tables 2,3 and 4, seven (six with IBR and one with NBR) had a personal history of allergic diseases. Only two patients (nos. 5 and 23) were mild asthmatics, both of whom had rarely had an episode of dyspnea in the previous 2 years. Seventeen patients (six, four and seven of each group, respectively) did not have any personal history of allergic diseases, high IgE level or positive mite-specific IgE antibody, which is the same condition as that of the control subjects in this study. None of them had

Table 2. Clinical data of patients with chest pain only upon exercise (Group 1) Patient

6 7 8 9 10 11

12 13

Age (years)

Sex

pc20 (mg/ml)

IgE (IU/ml)

RAST score

Eosinophil counts (per mm3)

8 12

F M F M M M F M M M M

< 0.78 < 0.78 0.90 1.25 1.35 1.75 1.76* 5.2* 18.0 23.0 27.0 >25.0* > 25.0

390 2050 506 30 100 75 29 550 95 187 69 120 180

4 3 3 0 0 2

396 53 1 375 180 140 225 92 180 82 336 216 72 72

10 10 14 9 15 12 14

I1 13 13

F

10

M

0 0

0 3 0 0 2

History of Allergy Personal Family AR, AD AD

-

BA

BA, bronchial asthma; AR, allergic rhinitis; AD, atopic dermatitis; b, brother; m, mother. *Chest pain was provoked during the methacholine challenge.

Vol. 34 No. 4 August 1992

444 (60) Iziimi el al. Table 3. Clinical data of patients with chest pain only at rest (Group 2) Patient

Age (years)

Sex

PCZO (mg/ml)

IgE (IU/ml)

14 15

9 10 10 10 9 13

F M M F M M M M

0.92 0.96 1.13 1.75 4.6 17.0 > 25.0 > 25.0

924 1321 610 39 40 80 I65 140

16 17 18 19 20 21

14

9

RAST score

Eosinophil counts (per mm’)

1

51 414 498 68 56 138 I08 79

4 3 0 0 0

-1

0

History of Allergy Personal Family AR -

RA, bronchial asthma: AR. allergic rhinitis: AD, atopic dermatitis; m. mother; b, brothec p, parent.

Table 4. Clinical data of patients with chest pain both upon exercise and at rest (Group 3) ~

Patient

-37 23 24 25 26 21 28 29 30 31

32

Age (years) 9 15 14

9 8 16

10 13 10

I2 13

Sex

M M F M F M F F M F M

PCzo (mg/ml) < 0.78* < 0.78 1.25* 1.75 1.85* 7.0

8.8* 13.0 >25.0* > 25.0 >3.0

IgE

RAST score

(IU/ml) I50 I695 1034 75 >700

0 3 4

185 10

I75 15

I70

13

-1

3 0 0

0 0 0 0

Eosinophil counts (per mm’) 180 474 390 225 305 50 47 I50 112 154

75

History of Allergy Personal Family

BA, AR AR -

-

-

BA (b) BA(gf) AR (m) AR (rn) BA, AR (f.b) -

-

BA (s) -

-

BA. bronchial asthma: AR. allergic rhinitis: b, brother: s. sister: f, father: rn, mother; gf. grandfather. *Chest pain was provoked during the methacholine challenge.

peripheral eosinophilia. From this 17, eight (47.1%; three, two and three of each group, respectively) had IBR. This incidence was also significantly higher than that in healthy controls ( P 90%) in Japan [ 161. An interesting question is why asthmatics who have more intense bronchial reactivity usually do not complain of chest pain whether they are having an attack or not. In one case, a patient experiencing intermittent typical bouts of asthma complained of tightness in her chest at times when her forced vital capacity, FEV,, blood gases and physical chest examination were normal except for increased airway resistance [ 171. By inhaling bronchodilators her complaint and abnormal airway resistance were relieved. The interpretation was that she had an isolated obstruction in the large airways (larger than 2 mm in diameter). Most patients had chest pains localized in some areas. Concerning this, regional ventilation defects have been demonstrated using radioisotope techniques in some asthmatics when they were in remission or attack [ 181. Myers et al. (1981) successfully treated their two patients with bronchodilators [6]. Though these were prescribed for some patients early in the present study, none of the patients could take medicine on a regular basis, and hence bronchodilators were not subsequently administered to the other patients. We do not claim that bronchial hyper-reactivity caused chest pain in all the patients who had IBR, but the incidence is very high and the challengeprovoked chest pain in eight patients. In the latter sense, recurrent pains occurring upon exerciseor both upon exerciseand at rest may more likely be due to bronchial hyper-

Vol. 34 No. 4 August I992

reactivity. We observed neither ECG nor blood pressure during MCH challenge, but all the provoked pains were promptly relieved by inhaling bronchodilators and all subjects had no abnormal findings at the examinations by the cardiologist, including exercise ECG tests. Although two patients with NBR were included in the eight who experienced provoked pain, this is not unexpected. It is demonstrated that some subjects with NBR have responsive airways, as demonstrated by distinct analysis ~91. In previous reports regarding the causes of chest pain and its incidences in children and adolescents, the leading cause is invariably idiopathic or unexplainable, accounting for from 21-55% of all cases [l-31. The present study demonstrates that bronchial hyperreactivity must be an important cause of this 'idiopathic' chest pain. Neither allergic examinations nor characteristics of chest pain were diagnostic for patients with IBR or those who provoked pains during inhalation challenge. Therefore, as inhalation challenge is used for other chest symptoms [20,21], patients with recurrent unexplained chest pain should also be considered for this procedure. References 1.

2. 3. 4.

5. 6. 7.

8.

Coleman WL. Recurrent chest pain in children. Pediatr Clin North Am 1984; 31: 1007-1026. Selbst SM, Ruddy RM, Clark BJ et al. Pediatric chest pain: A prospective study. Pediatrics 1988; 82: 319-323. Pantell RH, Goodman BW. Adolescent chest pain: A prospective study. Pediatrics 1983; 71: 881-887. Rowland TW, Richards MM. The natural history of idiopathic chest pain in children. A follow-up study. Clin Pediatr 1986; 25: 612-614. Fyfe DA, Moodie DS. Chest pain in pediatric patients presenting to a cardiac clinic. Clin Pediatr 1984; 23: 321-324. Myers JR, Corrao WM. Braman SS. Clinical applicability of a methacholine inhalational challenge. JAMA 1981: 246: 225-229. Izumi N, Nishio T, Haneda N et al. Chest pain as a manifestation of airway hyper-reactivity in children and adolescents. J Jpn Pediatr SOC 1987; 91: 3113-3117(inJpn). Nude1 DB, Diamant S, Brady T et al. Chest pain, dyspnea on exertion, and exercise-induced asthma in children and adolescents. Clin Pediatr 1987; 26: 388-392.

446 ( 6 2 ) Izumi et al. 9. Hargreave FE, Ryan G, Thomson NC et al. Bronchial responsiveness to histamine or methacholine in asthma: Measurement and clinical significance. J Allergy Clin lmmunol 198 1; 68: 347-355. 10. Chatham M. Bleecker ER, Smith PL et al. A comparison of histamine, methacholine and exercise airway reactivity in normal and asthmatic subjects. Am Rev Respir Dis 1982; 126: 235240. 1 I . Eggleston PE. A comparison of the asthmatic response to methacholine and exercise. J Allergy Clin Irnmunol 1979: 63: 104-1 10. 12. Cockcroft DW, Berscheid BA, Murdock KY. Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population. Chest 1983; 83: 751-754. 13. Hopp RJ, Bewtra AK, Nair NM et al. Specificity and sensitivity of rnethacholine inhalation challenge in normal and asthmatic children. J Allergy Clin Immunol 1984; 74: 154- 158. 14. Townley RG. Ryo UY. Kolotkin BM et al. Bronchial sensitivity to methacholine in current and former asthmatic and allergic rhinitis patients and control subjects. J Allergy Clin Immunol 1975: 56: 429-442.

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Masuda T, Naito A, Kinoshita M et al. Acetylcholine inhalation test in atopic dermatitis. J Allergy Clin Immunol 1967; 40: 193-201. Shibasaki M, Tajima K, Morikawa A et al. Relation between frequency of asthma and IgE antibody levels against Dermutophugoides furinue and total serum IgE levels in schoolchildren. J Allergy CIin Immunol 1988; 82; 86-94. F a n RS. Kopetzky MT, Spector SL et al. Asthma without wheezing. Chest 1973; 63 (Suppl. 4): S64-68. Uchiyama G, Sugimoto K, Hotta T et al. Pulmonary ventilation studies of asthmatic children with Kr-8 1m. Nippon Acta Radiologica 1979; 39: 499-505 (in Jpn). Hopp RJ,Weiss SJ, Nair NM et al. Interpretation of the results of methacholine inhalation challenge tests. J Allergy Clin Immunol 1987; 80: 821-830. Shapiro GG, Furukawa CT, Pierson WE et al. Methacholine bronchial challenge in children. J Allergy Clin Immunol 1982: 69: 365-369. Galvez RA, Mclaughlin FJ, Levison H. The role of the methacholine challenge in children with chronic cough. J Allergy Clin Immunol 1987; 79: 331-335.

Acta Paediatr Jpn

Methacholine inhalation challenge in children with idiopathic chest pain.

Bronchial reactivity to inhaled methacholine (MCH) was evaluated in 32 patients with 'idiopathic' chest pain. Each pain was recurrent in nature. The i...
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