Chest Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mochizuki, H.
Right arrow Articles by Morikawa, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mochizuki, H.
Right arrow Articles by Morikawa, A.
(Chest. 1999;116:619-624.)
© 1999 American College of Chest Physicians

Difference in Airway Reactivity in Children With Atopic vs Nonatopic Asthma*

Hiroyuki Mochizuki, MD; Makoto Shigeta, MD; Kenichi Tokuyama, MD and Akihiro Morikawa, MD

* From the Department of Pediatrics, Gunma University School of Medicine, Maebashi, Gunma, Japan.

Correspondence to: Hiroyuki Mochizuki, MD, Department of Pediatrics, Gunma University School of Medicine, 3–39-15 Showa-Machi, Maebashi, Gunma, 371-8411 Japan


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To examine the difference in the mechanisms of bronchial hyperresponsiveness (BHR) in nonatopic asthma and in atopic asthma, we studied bronchial reactivity against nonspecific stimuli in children with atopic asthma and nonatopic asthma.

Design and participants: Fourteen children with nonatopic asthma, 24 children with atopic asthma, and 20 age-matched controls participated in this study.

Measurements: Inhalation challenge was performed by administering progressively doubling doses of methacholine with a continuous inhalation provocation method. The speed of bronchoconstriction to methacholine (Sm) and the speed of reversal of bronchoconstriction to methacholine after inhalation of a ß2-agonist (r-Sm), which was considered to represent the effect of the ß2-agonist, were calculated from the dose-response curve.

Results: The value of Sm was higher in the nonatopic asthma group than in the atopic asthma group and the control group. The value of r-Sm was also higher in the nonatopic asthma group than in the atopic asthma group, but did not differ from that in the control group.

Conclusion: These results indicate that bronchial reactivity against methacholine and the ß2-agonist was greater in nonatopic asthma than in atopic asthma, and that the mechanism of BHR in children with nonatopic asthma may differ from that in children with atopic asthma.

Key Words: ß-agonist • bronchial hyperresponsiveness • nonatopic asthmatic children • methacholine inhalation challenge • oscillation technique


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Clinically , most children with asthma have the atopic type. Their family history of allergy is almost always positive, their serum IgE is usually high, and they react to the allergens by a skin test and by radioallergosorbent testing (RAST). However, some asthmatic children have neither any allergic history nor any family history of allergy. These children have so-called nonatopic asthma. The etiology of nonatopic asthma, while still obscure, is thought to be independent of allergic factors and/or airway mast cell activation.1 Although bronchial hyperresponsiveness (BHR) is also demonstrated in children with nonatopic asthma,2 it is possible that the fundamental mechanism of BHR in nonatopic asthma is different from that in atopic asthma.

We previously investigated the speed of bronchoconstriction in response to methacholine (Sm) in children with nonatopic asthma and reported that Sm was remarkably higher than in children with atopic asthma.3 It has been reported that Sm is dependent on the activity of the vagal nerve,4 and indicates the degree of bronchoconstriction, which reflects the isolated muscle tone.3 These results showed that children with nonatopic asthma had a high tone of the vagal nerve or bronchial muscles, the etiology of which was independent of allergic inflammation. However, the precise mechanism of nonatopic asthma remains unclear and further research is required. Therefore, in this study, we noted the speed of reversal of bronchoconstriction to distinguish between the two types of asthma.

The suitability of the forced oscillation technique for the assessment of children with asthma has been studied.5 6 7 This method, which can be used during tidal breathing, gives a good correlation between the severity of bronchial asthma and BHR,8 and has the advantage that respiratory resistance (Rrs) can be measured continuously, allowing precise changes in Rrs to be detected. We have reported the forced oscillation method as an objective method to evaluate the effect of inhaled ß2-agonists against bronchoconstriction by measuring the speed of reversal of bronchoconstriction in response to methacholine (r-Sm).9

The purpose of this study was to evaluate the difference in mechanism of BHR between children with nonatopic asthma and children with atopic asthma by measuring the bronchial reactivity against nonspecific stimuli: a bronchoconstrictor and a bronchodilator. We studied the change in Rrs throughout the methacholine inhalation challenge in children with nonatopic asthma, children with atopic asthma, and age-matched controls, and calculated the parameters related to bronchial reactivity in each of the three groups.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
Sixteen children with nonatopic asthma (seven boys and nine girls from 6 to 16 years of age) were entered in this study. For comparison, 25 age-, height- and Rrs-matched children with atopic asthma (15 boys and 10 girls from 6 to 16 years of age) and 20 age-matched control children without respiratory disease (eight boys and 12 girls from 6 to 16 years of age) were entered in this study (Table 1 ). The clinical diagnosis of bronchial asthma was based, after more than a year of follow-up observation, on a characteristic history of recurrent attacks of dyspnea with perceptible wheezing. All subjects with atopic asthma reacted to common environmental allergens administrated to the skin and to RAST (development of a wheal 5 mm or larger in a prick test and more than 0.70 Phadebas RAST unit). None of the children with nonatopic asthma had a personal allergic history or a family history of allergic disease within the third degree, and these children did not react to more than 10 common allergens administered to the skin or to RAST. The tests were performed when baseline FEV1 was > 70% of predicted.


View this table:
[in this window]
[in a new window]

  		Table 1. Characteristics of Study Subjects*

 
None of the children were receiving regular inhaled ß2-agonists or corticosteroid therapy. All subjects were free of upper respiratory tract infections for more than 4 weeks prior to the start of each study, and received no medication for at least 12 h prior to testing. Informed parental consent was obtained before the study.

Methacholine Inhalation Challenge
Methacholine inhalation challenges were performed according to the procedure described by Takishima.10 11 An aerosol generator (Astrograph TCK61001t; Chest Co.; Tokyo, Japan) delivered increasing doses of methacholine from 12 serially arranged nebulizers. The nebulizers were activated by a constant air flow of 5 L/min generated by an air compressor. The air flow was switched from one nebulizer to the next at predetermined intervals. Each nebulizer delivered approximately 0.15 mL of solution per minute with increasing concentrations of methacholine and a bronchodilator.

Bronchial responsiveness was displayed in the form of a continuous record of the Rrs, measured by the oscillation technique. A constant-amplitude pressure generator was connected to a mouthpiece and produced a constant-amplitude sinusoidal pressure wave of 2 cm H2O of 7 Hz at the mouth. Recordings showing excessive fluctuations, especially those caused by coughing, were excluded after two independent examiners agreed that such records were not suitable for evaluating BHR.

Methacholine (Daiichi Kagaku Yakuhin Co; Tokyo, Japan), prepared on the day of the test, was serially diluted twofold with saline solution (10 dose steps starting from a concentration of 25 mg/mL down to approximately 49 µg/mL). The first nebulizer contained 2 mL saline solution; the second nebulizer contained 2 mL of the weakest dilution of methacholine; the third to 10th nebulizers contained increasing concentrations of methacholine. Each concentration of the methacholine solution was inhaled for 1 min. The 11th nebulizer contained salbutamol hemisulfate (1.7 mg/mL in saline solution), which was inhaled for 2 min.

Subjects were examined during quiet breathing in a sitting position with a nose clip attached and two air-filled balloons placed at both sides of the cheeks, and doses of inhaled methacholine were doubled every minute. When the Rrs reached double the baseline value, methacholine inhalation was stopped, and salbutamol solution was inhaled for 2 min. The total amount of nebulized salbutamol was approximately 0.5 mg. Rrs was continuously measured until it reached a stable state.

We calculated four parameters in the Rrs dose-response curve (Fig 1 ). First, we calculated the linear slope of Rrs increase (Sm), which represents the speed of bronchoconstriction in response to methacholine. The second parameter was the linear slope of Rrs decrease after ß2-agonist inhalation (r-Sm), which is considered to represent the time course of the direct effect with inhaled ß2-agonist9 (that is, the speed of reversal of bronchoconstriction). Also, two common parameters were calculated: the control value of Rrs, and the minimum dose of methacholine causing bronchoconstriction (Dmin; ie, the cumulative dose of methacholine at the inflection point of the Rrs tracing, representing bronchial sensitivity).7 One Dmin unit is equal to 1 min of inhaling an aerosolized methacholine solution of 1.0 mg/mL during tidal breathing.



View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. The dose-response curve of Rrs in methacholine inhalation challenge using the oscillation method. Rrs increased with inhalation of incremental amounts of methacholine. When Rrs reached about twice the baseline value, inhalation of methacholine was stopped and a ß2-agonist was inhaled. Four parameters were calculated: control value of Rrs (Rrs.cont), Dmin, Sm, and r-Sm. BD = bronchodilator inhalation.

 
Data Analysis
The nonparametric analysis of variance (Kruskal-Wallis method) was used to determine the significant variances among the three groups. If a significant overall difference was found, the Mann-Whitney U-test was performed to assess the significant difference between individual groups. Single regression analysis between r-Sm and Sm was performed in each group. The logarithmic values of Dmin, log10 (milliunits), were used for statistical analysis. For convenience, data are expressed as mean ± SD.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Two of the 16 children with nonatopic asthma (an 8-year-old boy and an 11-year-old girl) were excluded because their recordings showed excessive fluctuations and they became uncooperative during the inhalation test. For the same reasons, one of 25 atopic asthmatic subjects was excluded (an 11-year-old girl). Consequently, 14 children with nonatopic asthma (six boys and eight girls) and 24 children with atopic asthma (15 boys and nine girls) participated in this study, along with 20 age-matched children (eight boys and 12 girls) who served as a control group, (Table 1) .

Figure 2 illustrates the typical Rrs curves in each of the three groups. In children with nonatopic asthma and atopic asthma, r-Sm was significantly lower than Sm (p < 0.01 for each group), and r-Sm correlated with Sm (p < 0.01 for each group), although other parameters did not correlate with r-Sm. In children in the age-matched control group, r-Sm was significantly higher than Sm (p < 0.001), and r-Sm correlated with Sm (p < 0.001).



View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. The typical dose-response curve of Rrs in each of the three groups. Top, a: atopic asthma group. Center, b: nonatopic asthma group. Bottom, c: age-matched control group. BD = bronchodilator inhalation.

 
There were no significant differences among the three groups in the control value of Rrs (Table 2 ). The atopic asthma and nonatopic asthma groups' values of Dmin were higher than the control group's (p < 0.01 and p < 0.05, respectively), which is consistent with previous reports.3 There was no significant difference in Dmin between the atopic and nonatopic asthma groups. Sm was higher in the nonatopic asthma group than in either the atopic asthma group or the control group (p < 0.05 and p < 0.005, respectively), which is consistent with previous reports.3 The r-Sm values were significantly higher in the nonatopic asthma group and the control group than in the atopic asthma group (p < 0.005 for each group). For r-Sm, there was no significant difference between the nonatopic asthma group and the control group (Fig 3 ).


View this table:
[in this window]
[in a new window]

  		Table 2. Results of Methacholine Inhalation Challenge in Atopic Asthma, Nonatopic Asthma, and Control Groups*

 


View larger version (48K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. The values of Sm and r-Sm in the atopic asthma, nonatopic asthma, and age-matched control groups. N.S. = not significant.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In contrast to allergic asthma, relatively little is known of the mechanisms contributing to the pathogenesis of nonatopic asthma. Sometimes, the names intrinsic asthma and infectious asthma have been used for nonatopic asthma, and it is true that viral infections of the respiratory tract produce an increase in nonspecific airway responsiveness in normal subjects. Also, a relationship between allergic reaction and viral infection has been reported; ie, in asthma associated with atopy, infectious reactions become greatly exaggerated by interaction with an already present allergic inflammatory process12 13 However, the mechanism of long-term continuous BHR in nonatopic asthma has not been demonstrated in these reports and remains unclear.

We have reported that the bronchial sensitivity (Dmin) of children with atopic asthma was no different from that of children with nonatopic asthma.3 This was in close agreement with another study reporting that there were no differences in bronchial sensitivity among adults with atopic, infectious, and mixed asthma.14 However, we have also reported the differences between the two types of asthma: Nonatopic asthma appears at a relatively older age and is clinically more severe than atopic asthma, and the speed of bronchoconstriction is significantly higher in children with nonatopic asthma than in children with atopic asthma.3

In this study, we noted the difference in both Sm and r-Sm between the two types of asthma by observing Rrs changes measured using the oscillation technique, which has been used for the evaluation of smooth muscle reactivity induced by ß2-receptor stimulation.9 We successfully demonstrated that Sm and r-Sm are greater in nonatopic asthma than in atopic asthma.

Previously, we have documented that Sm is markedly higher in children with nonatopic asthma than in children with atopic asthma, a finding which may reflect the isolated muscle tone.3 In this study, the airway smooth muscle may have a higher reactivity in children with nonatopic asthma than in children with atopic asthma, resulting in good reactivity against nonspecific stimuli, such as muscarinic and adrenergic stimulation. These data suggest that the hyperreactivity of airway smooth muscle may be one of the fundamental mechanisms of BHR in nonatopic asthma, and that it has an effect on the exacerbation of nonatopic asthma. However, further research is needed because it is still unclear whether it is smooth muscle fiber itself or the number or kind of receptors on the muscle that has the most effect.

On the other hand, we have reported that r-Sm was lower in children with atopic asthma than in children with chronic cough (p < 0.001), whereas there was no Sm difference between children with atopic asthma and those with chronic cough.9 The values of Sm and r-Sm in children with chronic cough were 2.22 ± 0.3 cm/H2O/L/s/min and 3.71±0.6 cm/H2O/L/s/min, which were almost the same as the values in the control group. It is thought that there may be a reduced response to inhaled ß2-agonist in children with atopic asthma because of the dysfunction of airway ß2 receptors.15 Although the acquired dysfunction, downregulation, or decoupling may be induced by asthma therapy using ß2-agonists, there was no difference in asthma therapy, nor any difference in the severity of asthma and BHR, between the atopic and nonatopic asthma groups in this report. Furthermore, none of these children were regularly receiving inhaled ß2-agonists, nor had they received oral ß2-agonists for at least 12 h prior to testing. Thus, children with atopic asthma have a low reactivity to inhaled ß2-agonist despite asthma therapy, a finding suggested in previous reports.16 17

Another possible mechanism for the reduced response in children with atopic asthma is that airway secretion and edema induced by inhaled methacholine should have greater effects on r-Sm in atopic asthma than in nonatopic asthma, although the reactivity of airway smooth muscle may play a role in this phenomenon. Bronchoconstriction during methacholine inhalation challenge is directly caused by the stimulation of the muscarinic receptors on airway smooth muscle, and is indirectly caused by stimulation of airway glands, airway epithelium, and sensory nerves,18 which induce edema or secretion in airways. It has been demonstrated that the presence of chronic allergic inflammation in airway mucosa plays a role in recurrent asthma attacks in atopic asthma,19 20 which may allow airway secretion and edema to be easily induced by inhaled methacholine. On the other hand, there is no chronic allergic inflammation in nonatopic asthma, and the rapid secretion and/or edema in airway mucosa may not be induced. The presence of edema or secretion in airway mucosa in atopic asthma may have some effects on r-Sm, and this may be one of the differences in the mechanism of BHR in children with atopic asthma vs children with nonatopic asthma.

In summary, we have shown that the inhaled methacholine and ß2-agonist were more effective in the nonatopic asthma group than in the atopic asthma group, and that the fundamental mechanism of nonatopic asthma is different from that of atopic asthma. However, the exacerbation of asthma attack by respiratory infections and the improvement of asthma with inhaled steroid therapy is demonstrated in both types of asthma in children, because both disease types demonstrate BHR. Further investigations will be needed to clarify the mechanisms that induce high reactivity of airways in children with nonatopic asthma.


   Footnotes
 
Abbreviations: BHR = bronchial hyperresponsiveness; Dmin = minimal dose of methacholine; RAST =radioallergosorbent testing; Rrs = respiratory resistance; r-Sm = speed of reversal of bronchoconstriction in response to methacholine; Sm = speed of bronchoconstriction in response to methacholine

Received for publication September 16, 1998. Accepted for publication April 13, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Wenzel, SE, Fowler, AA, III, Schwarts, LB (1988) Activation of pulmonary mast cells by bronchoalveolar allergen challenge: in vivo release of histamine and tryptase in atopic subjects with and without asthma. Am Rev Respir Dis 137,1002-1008[ISI][Medline]
  2. Shimizu, H, Mochizuki, H, Morikawa, A, et al (1993) Inhaled furosemide prevents ultrasonically nebulized water bronchoconstriction in children with both atopic and nonatopic asthma. Chest 104,1723-1726[Abstract/Free Full Text]
  3. Mochizuki, H, Mitsuhashi, M, Shigeta, M, et al (1987) Bronchial hyperresponsiveness in children with atopic and nonatopic asthma. J Asthma 24,75-80[Medline]
  4. Milles, JE, Sellik, M, Widdicombe, JG (1969) Activity of lung irritant receptors in pulmonary microembolism, anaphylaxis and drug-induced bronchoconstriction. J Physiol 203,337-357[Abstract/Free Full Text]
  5. Cogswell, JJ (1973) Forced oscillation technique for determination of resistance to breathing in children. Arch Dis Child 48,259-266[ISI][Medline]
  6. Wanner A, Zarzecki S, Marks MB. Continuous measurement of respiratory resistance in asthmatic children. 1977; 32:61–68
  7. Mochizuki, H, Mitsuhashi, M, Tokuyama, K, et al (1988) Bronchial hyperresponsiveness in younger children with asthma. Ann Allergy 60,103-106[Medline]
  8. Mochizuki, H, Mitsuhashi, M, Tokuyama, K, et al (1985) A new method of estimating bronchial hyper-responsiveness in younger children. Ann Allergy 55,162-166[Medline]
  9. Mochizuki, H, Shigeta, M, Arakawa, H, et al (1997) Difference of inhaled ß2-agonist effect in respiratory resistance between asthmatic children and children with chronic cough [in Japanese]. Jpn J Pediatr Pulmonol 8,20-26
  10. Takishima, T, Hida, W, Sasaki, H, et al (1981) Direct-writing recorder of the dose-response curves of the airway to methacholine. Chest 80,600-606[Abstract/Free Full Text]
  11. Takishima, T, Hida, W, Suzuki, S, et al (1981) Direct graphical recordings of the cumulative dose-response curves of the airway to methacholine in normal, bronchitis and asthmatic subjects. Tohoku J Exp Med 35,117-137
  12. Goetzl, EJ (1981) Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation. Med Clin North Am 65,809-828[Medline]
  13. Stempel, DA, Boucher, RC (1981) Respiratory infection and airway reactivity. Med Clin North Am 65,1045-1053[Medline]
  14. Iijima, M, Adachi, M, Kobayashi, H, et al (1985) Relationship between airway hyperreactivity and various atopic factors in bronchial asthma. Arerugi 34,226-233[Medline]
  15. Nijkamp, FP, Engels, F, Henricks, PAJ, et al (1992) Mechanisms of ß-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev 72,323-367[Free Full Text]
  16. Szentivanyi, A (1968) The beta adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 42,203-232[CrossRef][ISI]
  17. Shelhamer, JH, Metcalfe, DD, Smith, LJ, et al (1980) Abnormal beta adrenergic responsiveness in allergic subjects: analysis of isoproterenol-induced cardiovascular and plasma cyclic adenosine monophosphate responses. J Allergy Clin Immunol 66,52-60[Medline]
  18. Mochizuki, H, Shigeta, M, Kato, M, et al (1995) Age-related changes of bronchial hyperresponsiveness to methacholine in asthmatic children. Am J Respir Crit Care Med 152,906-910[Abstract]
  19. Laitinen, LA, Heino, M, Laitinen, A, et al (1985) Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 131,599-606[ISI][Medline]
  20. Busse, WW (1989) The role of inflammation in asthma: a new focus. J Respir Dis 10,72-80




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mochizuki, H.
Right arrow Articles by Morikawa, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mochizuki, H.
Right arrow Articles by Morikawa, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS