PEDIATRICS Vol. 106 No. 6 December 2000, pp. 1442-1446

Bronchial Hyperresponsiveness Before and After the Diagnosis of Bronchial Asthma in Children

Hiroyuki Mochizuki, MD^*, Makoto Shigeta, MD, Hirokazu Arakawa, MD^*, Masahiko Kato, MD^*, Kenichi Tokuyama, MD^*, and Akihiro Morikawa, MD

From the ^* Department of Pediatrics, Gunma University School of Medicine, Maebashi, Gunma, Japan; and  Division of Allergy, Gunma Children's Medical Center, Hokkitu, Gunma, Japan.

	ABSTRACT

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Objective.  To assess at what age bronchial hyperresponsiveness (BHR) is acquired in children with asthma.

Background.  A relationship between BHR and infantile wheezing diseases has been reported. Infants with a genetic predisposition to atopy are more likely to wheeze with respiratory viral infection or bronchiolitis, and it is suspected that the continued BHR after the first attack of asthma may be induced or triggered by some viral infections. Also, recent studies have reported the existence of atopic and BHR-related genes. However, whether BHR is congenital or acquired after asthma attacks, and when BHR in children with asthma is established or acquired remain unclear.

Methods.  We performed methacholine inhalation challenge using a transcutaneous oxygen pressure (tcPO₂) monitoring system in 205 children without asthma from 6 months to 6 years of age. During follow-up, 18 of these participants were diagnosed with asthma (group N-A). This group and 15 age-matched children without asthma (group N-N) were tested twice using methacholine inhalation challenge. For comparison, 39 age-matched atopic-type asthmatic children (group A-A) were also given the inhalation challenge twice. Methacholine inhalation challenge using a tcPO₂ monitoring system was performed while the participants were asleep in the supine position. Sequential doses of inhaled methacholine delivered by oxygen mask were doubled until a 10% decrease in tcPO₂ from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO₂ (minimal dose of methacholine [Dmin]-PO₂) was considered to represent BHR.

Results.  In groups N-N and A-A, there was no difference in Dmin-PO₂ between the first and second challenge. However, the Dmin-PO₂ in group N-A significantly decreased from the first challenge to the second challenge. There was no significant difference between the Dmin-PO₂ in group N-N and the first Dmin-PO₂ in group N-A; or between the Dmin-PO₂ in group A-A and the second Dmin-PO₂ in group N-A.

Conclusions.  These data suggest that BHR in many infants with asthma is acquired after several asthma attacks.bronchial hyperresponsiveness, childhood asthma, methacholine inhalation challenge, transcutaneous oxygen pressure.

Asthma is the most common chronic disease of children, and the association between asthma and bronchial hyperresponsiveness (BHR) has been well-demonstrated. The degree of BHR shows a good correlation with the severity of the asthmatic symptoms,^1,2 but when and how BHR in children with asthma is established or acquired is still unclear.

A relationship between BHR and infantile wheezy diseases has been reported. Infants with a genetic predisposition to atopy are more likely to wheeze with respiratory viral infection or bronchiolitis.³ Also, viral bronchiolitis might contribute to the development of subsequent wheezing, or the illness diagnosed as bronchiolitis may be an early marker of genetically determined asthma.⁴ Generally, viral infections exacerbate BHR,⁵ and it is suspected that the continued BHR after the first attack of asthma may be induced or triggered by some viral infections. Recent studies^6,7 have reported the existence of atopic and BHR-related genes. However, whether BHR is congenital or acquired after several asthma attacks is still unclear: a large prospective study is needed to solve this problem.

Previously, we described a technique of evaluating BHR, by monitoring transcutaneous oxygen pressure (tcPO₂), which can be used over a wide age range in childhood.^8-10 In this study, to assess when BHR is acquired in children with asthma, we performed methacholine inhalation challenge by using this technique in children without asthma and measured BHR once again after they were diagnosed with asthma, and compared the results. Age-matched disease controls without asthma and age-matched children with asthma also participated in this study.

	METHODS

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Study Participants

We performed methacholine inhalation challenge on Japanese children without asthma. We informed all of the outpatients at Gunma University Hospital, Department of Pediatrics, Division of Allergy, Infection, Respiration and Cardiology of our study, and were permitted to undertake the methacholine inhalation test by their doctors. We discussed the procedures thoroughly with the parents of all children before the study, who gave their informed consent, and performed the methacholine inhalation challenge on 205 children without asthma from June 1983 to November 1997. Of these, 133 (65%) have a family history of allergies. During 1 or more years of follow-up, 18 of these participants demonstrated 2 or more episodes of wheezing and dyspnea (Table 1). All 18 participants had shown positive skin tests and/or radioallergosorbent tests, and were diagnosed as having atopic-type asthma.

Informed parental consent to undertake a second methacholine inhalation challenge after an interval of 1 year or more was obtained from the parents of the 18 participants diagnosed with asthma after the first inhalation challenge (group N-A; Table 1). The diagnoses at the first visit (patient numbers) were: chronic cough⁸; diagnosed as having 8 weeks or more of continued cough without wheezing and respiratory infections; siblings of children with asthma⁴; cough³; diagnosed as having <8 weeks of continued cough without wheezing; atopic dermatitis²; and allergic conjunctivitis.¹ Fifteen age-matched controls without asthma (group N-N), and 39 age-matched atopic-type asthmatic children (group A-A) were enrolled in this study (Table 2). None of these children were receiving steroid therapy, and none had received any medication for at least 12 hours before the inhalation challenge. They had been free of upper respiratory tract infections for >4 weeks before the start of each study. Also, all of their parents were directed to forbid smoking at home and to keep the home clean from air pollutants as much as possible during follow-ups.

Methacholine Inhalation Challenge

Methacholine inhalation challenge was performed twice on all of the participants in the 3 groups. A previously described tcPO₂ monitoring system was used to measure the results.^8,11 The challenge was performed while the participants were sleeping in the supine position after trichlorethyl phosphate monosodium syrup (70 mg/kg) was administered.

Each methacholine inhalation challenge was performed using Takishima's procedure described elsewhere.¹¹ Briefly, the methacholine, (Daiichi Kagaku Yakuhin Co, Tokyo, Japan), which was prepared on the day of the test, was serially diluted twofold with saline (10 dose steps from 25 mg/mL to ~49 µg/ml) and administered via an Astograph used as the delivery system. The system consisted of 12 identical nebulizers connected to a main tube and an air compressor that switched from one nebulizer to another automatically at 1-minute intervals. Study participants inhaled methacholine mist using an oxygen mask with a constant bias flow that was connected to the main tube of an Astograph. Saline was used in the first nebulizer as a control. Salbutamol hemisulfate was used in the final nebulizer to treat the induced bronchoconstriction (Fig 1).

View larger version (16K): [in this window] [in a new window]   Fig. 1.   The dose-response curve of tcPO2 during methacholine inhalation challenge in a typical case. With inhalation of incremental amounts of methacholine, tcPO2 gradually decreased. BD: bronchodilator inhalation.

tcPO₂ was measured using a tcPO₂ monitoring system (Cutaneous PO₂ Monitor 820, Roche, Switzerland). The sensor temperature was fixed at 45°C and placed on the anterior part of the forearm.

Subsequent doses were doubled, until a 10% decrease in tcPO₂ from the baseline was reached. The cumulative dose of methacholine administered at the inflection point where tcPO₂ decreased linearly (minimal dose of methacholine [Dmin]-PO₂) was taken as the reactivity of tcPO₂ to methacholine, which was significantly related to the change of respiratory resistance (Rrs) (Dmin-Rrs) obtained from the oscillation method in children.⁸ One Dmin unit was considered to be equal to 1 minute of inhaling an aerosolized methacholine solution (1.0 mg/ml) during tidal breathing.

In the present study, the Dmin-PO₂ of participants who could successively inhale the maximum dose of methacholine without a significant decrease in tcPO₂ was calculated to be 49.952 units, which was the maximum cumulative dose of methacholine.

Data Analysis

The nonparametric analysis of variance (Kruskal-Wallis method) was used to determine the significant variance among the 3 groups. A Mann-Whitney U test was performed to assess the significant difference between paired groups. For convenience, data are expressed as means ±SD. P values <.05 were considered to be significant.

	RESULTS

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There was no difference in the mean age among the children in the 3 groups either at the first trial or at the second trial (Kruskal-Wallis method). In group N-N, there was no difference in Dmin-PO₂ between the first and second challenge (16.6 units and 20.5 units, respectively, Mann-Whitney U test). Also, in group A-A, there was no difference in Dmin-PO₂ between the first and second challenge (5.2 units and 5.3 units, respectively). However, Dmin-PO₂ in group N-A was decreased significantly from the first challenge (19.4 units) to the second challenge (2.8 units, P < .001) (Fig 2). There was no significant difference between Dmin-PO₂ in group N-N and the first Dmin-PO₂ in group N-A; or also between Dmin-PO₂ in group A-A and the second Dmin-PO₂ in group N-A (Kruskal-Wallis method).

View larger version (18K): [in this window] [in a new window]   Fig. 2.   Results for methacholine inhalation challenge at the first and second trials in 3 groups; patients without asthma (group N-N), patients diagnosed with asthma after the first trial (group N-A), and patients diagnosed with asthma before the first trial (group A-A). Each vertical bar is SEM.

In group N-A, there was no difference between Dmin-PO₂ in the first challenge in the male and that in the female group, and between Dmin-PO₂ in the second challenge in the male and that in the female group. Also, in group N-A, the change in Dmin-PO₂ in the male group (n = 14, from 14.8 to 2.6 units) was not significantly different from that in the female group (n = 4, from 27.7 to 4.0 units), (Mann-Whitney U test).

	DISCUSSION

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It has been hypothesized that nonspecific BHR is a risk factor in accelerated pulmonary function decline during aging and in the development of chronic airflow obstruction.^12,13 Also, large prospective studies have suggested that the degree of BHR is one of the significant variables that predicts persistent symptoms. A strong association has been found between the presence and degree of BHR and the need for medication in adulthood.^14,15 In other words, BHR indicates the asthma prognosis. These results suggest the possibility that BHR has an effect on asthmatic symptoms in childhood. However, the basic problems of when and how BHR in children with asthma is acquired, and whether BHR universally precedes the onset of asthma or not, is still under discussion.

It has been reported that BHR is already present in very young children, and that asymptomatic infants demonstrating BHR will subsequently develop asthma.¹⁶ These findings are consistent with the theory that infants are either born with BHR or develop it soon after birth. Also, previous investigations have suggested that participants with asymptomatic BHR had a greater frequency of developing asthma symptoms than did normal responsive participants.^15-21 A longitudinal population study showed an increase in the prevalence of asthma with asymptomatic BHR, and that BHR is a more important risk factor for the development of asthma than other atopic symptoms.²² However, the number of participants in these reports, in which BHR was measured by using V'max functional reserve capacity^16,21 was small. Also, in longitudinal population studies, study participants were young adults or children >6 years old.^15,17-20 We believe that it is important to measure BHR in children <6 years old, because previous reports have shown that the first attack of asthma frequently occurs within the first few years of life, and that 80% of children develop symptoms before the age of 5.²³

To solve the problem of BHR onset in children with asthma, a large longitudinal study and a simple, safe, and reliable technique for measuring infantile BHR is required. The assessment of BHR in infants has not been uniformly successful, and measurements of BHR over the childhood period are associated with a number of problems. Some previous reports have recommended the use of provocation tests using tcPO₂ or oxygen saturation.^21,24-29 Previously, we studied a technique of evaluating the BHR in infants with asthma by monitoring tcPO₂.⁸ During an acute attack of asthma, tcPO₂ correlates lineally to the severity of the attack. Methacholine-induced airway obstruction results in hypoxia because the narrowing of the airways changes the local ventilation/perfusion ratio and results in decreased arterial PO₂. Although this tcPO₂ change only reflects the indirect caliber change, we have demonstrated that this method is simple, painless, and effort independent with high reproducibility, which means that it is suitable for use with infants.⁹ Van Broekhoven and Wilts also reported measurement of BHR using the tcPO₂ method in younger children, and suggested its convenience and safety.^24,25

Using this technique, we demonstrated that BHR in most children who will develop asthma is not detectable before asthma attacks, but it is observable after at least the second attack in children with asthma. Our results differed from some previous reports, which indicate a relationship between silent BHR and the development of asthma. However, in our results, patients 6, 7, and 8 previously exhibited BHR at the first inhalation challenge. Therefore, it is thought that in most children who go on to develop asthma, BHR is not detected before asthma attacks, and that some of these children demonstrate silent BHR. However, in this study, we were not able to distinguish between these 2 groups by family history, past history, skin tests, or radioallergosorbent tests. Another possible explanation for the difference between our results and the results of others may be resulting from our choices, which were a large sample number, younger participants and a suitable method for measuring infantile BHR.

In this report, all infants diagnosed with asthma had the atopic type. One can speculate that atopic-type infants have a congenital predisposition to acquire BHR. It seems to occur more frequently in the presence of atopy, and many patients with allergic rhinitis and other atopic diseases have increased BHR.³⁰ Duiverman et al³¹ demonstrated that children without asthma, but with borderline BHR, had a family history of asthma, and that asthmatic children with a relatively low degree of BHR had no family history of asthma. Heredity as a factor in BHR is also suggested in the studies of twins³² and familial aggregation of BHR.³³ There is clearly an hereditary component in BHR because a family history of atopy is the most important risk factor for atopy in children, and childhood asthma is linked to a family history of atopy.³⁴ Allergy and BHR may be related by genetically-linked traits, chronic inflammatory processes, or both.

Our results suggest that infants who develop asthma may not have shown clinical BHR at birth, but that BHR is clearly present after asthma has been diagnosed. Considering these results, we hypothesize that BHR is not a necessary precursor to the first attack of childhood asthma, although BHR is a factor in the exacerbation of childhood asthma. According to previous reports, factors such as atopy, gender, and respiratory infections in early life are closely associated with the onset of childhood asthma and play important roles in the acquirement of BHR.^35,36 We believe that some of these factors may turn on the BHR switch in the children who are predisposed to having asthma, and the activated BHR exacerbates childhood asthma for the long-term. However, persistent BHR depends not only on individual predisposition, but also on the cause. In this report, we cannot define the precise mechanisms by which BHR in children with asthma persists for long periods: further investigation is needed.

	FOOTNOTES

Received for publication Jan 31, 2000; accepted Apr 17, 2000.

Reprint requests to (H.M.) Department of Pediatrics, Gunma University School of Medicine, 3-39-15 Showa-Machi, Maebashi, Japan 371-8511. E-mail: mochihi{at}akagi.sb.gunma-u.ac.jp

	ABBREVIATIONS

BHR, bronchial hyperresponsiveness; tcPO₂, transcutaneous oxygen pressure; Dmin, minimal dose of methacholine; Rrs, respiratory resistance.

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