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(Chest. 2003;124:819-825.)
© 2003 American College of Chest Physicians

Bronchial Hyperresponsiveness in Adolescents With Long-term Asthma Remission*

Importance of a Family History of Bronchial Hyperresponsiveness

Young Yull Koh, MD; Eun Kyeong Kang, MD; Hee Kang, MD; Young Yoo, MD; Yang Park, MD and Chang Keun Kim, MD

* From the Department of Pediatrics and Clinical Research Institute (Drs. Koh, E.K. Kang, H. Kang, Yoo, and Park), Seoul National University Hospital, Seoul; and Department of Pediatrics (Dr. Kim), Inje University Sanggye Paik Hospital, Seoul, Korea.

Correspondence to: Young Yull Koh, MD, Department of Pediatrics, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea; e-mail: kohyy{at}plaza.snu.ac.kr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The mechanisms responsible for bronchial hyperresponsiveness (BHR) in symptomatic asthma include genetic predisposition and airway inflammation, but the causes of BHR in adolescents with asthma remission are poorly understood. It has been shown that BHR in adolescents with asthma remission was not reduced by prolonged treatment with inhaled corticosteroids, in contrast to the BHR of symptomatic asthma.

Objective: The aim of this study was to investigate whether family history of BHR may contribute to the persistence of BHR in asthma remission during adolescence.

Methods: One hundred twenty-six adolescents with long-term asthma remission (neither symptoms nor any medication used during the previous 2 years) and their parents underwent a methacholine inhalation test. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and the bronchial responsiveness (BR) index were calculated for each individual.

Results: Sixty-nine adolescents (54.8%) were found to have persisting BHR (PC20 < 18 mg/mL). The frequency of BHR and the BR index were significantly higher in parents (n = 138) of the BHR-persisting group (28.3% and 1.150 ± 0.103, respectively [mean ± 1 SD]) than in parents (n = 114) of BHR-nonpersisting group (16.7% [p = 0.030] and 1.124 ± 0.088 [p = 0.029], respectively). Furthermore, adolescents (n = 56) with at least one BHR-positive parent were found to have a higher frequency of BHR (66.1% vs 45.7%, p = 0.023) and a higher BR index (1.244 ± 0.090 vs 1.204 ± 0.082, p = 0.011) than adolescents (n = 70) with non-BHR parents.

Conclusion: Our results suggest that adolescents in asthma remission are more likely to have BHR when there is a family history of BHR. Further studies are needed to examine the possible involvement of genetic factors in the BHR of adolescents in asthma remission.

Key Words: adolescent • asthma • bronchial hyperresponsiveness • bronchial responsiveness index • clinical remission • family history


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Epidemiologic studies1 2 have demonstrated that many asthmatic children go into long-lasting clinical remission at adolescence. Bronchial hyperresponsiveness (BHR), often called "the hallmark of asthma," is known to be an important risk factor for the development of asthma3 and to be indicative of asthma severity with respect to symptomatic asthma4 ; however, several studies5 6 have shown that BHR persists in a considerable proportion of adolescents with asthma in long-term clinical remission, although the degree of BHR is not as severe as that in patients with symptomatic asthma.7

Little is known about the mechanism underlying BHR in adolescents with asthma remission. BHR in symptomatic asthma is thought to be a consequence of the underlying airway inflammation,8 and several studies9 10 have noted correlations between measurements of bronchial responsiveness and various aspects of cellular airway inflammation; however, it is not known whether the persisting BHR of adolescents with asthma remission is also associated with airway inflammation or linked to another mechanism. We have shown11 12 that inhaled budesonide did not cause a significant BHR reduction in this clinical setting, which is in contrast to the BHR of symptomatic asthma. This raises a question about the hypothesis that airway inflammation plays an important role in the BHR of adolescents with asthma remission, since BHR reduction by corticosteroids is mainly due to an improvement in various measures of airway inflammation.13

The importance of a familial predisposition in BHR and, therefore, a possible genetic transmission of BHR have been shown by several studies.14 15 BHR in asthma is thus presumed to reflect the contribution of two components, wherein one is related to airway inflammation and the other is to intrinsic BHR,16 and a number of arguments have been proposed suggesting that this intrinsic BHR is under genetic control.17 18

We hypothesized that the BHR of adolescents in asthma remission may be related to the intrinsic BHR of each individual, and thus may be controlled by genetic factors. Specifically, we wanted to test the hypothesis that the persistence of BHR in clinical remission during adolescence is dependent on the family history of BHR. In order to test this hypothesis, we performed a methacholine challenge test in the parents of adolescents in asthma remission, and analyzed the results with regard to the BHR status of their children.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Adolescents in long-term atopic asthma remission and their parents were targeted for this study. The adolescents, 13 to 17 years of age, were selected from the Seoul National University Children’s Hospital allergy clinic. All subjects had a history of wheezing and dyspnea, and had previously received a diagnosis of atopic asthma according to the American Thoracic Society criteria.19 In the past, all were recorded to have a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of < 18 mg/mL. Other chronic obstructive airway disorders had been excluded by relevant investigations in all subjects. Atopy was defined as at least one positive skin-prick test response in a panel of 12 common aeroallergens, in the presence of positive and negative controls. The majority of subjects showed a positive skin reaction to house dust mites. Long-term clinical remission was assumed if subjects reported the complete absence of wheezing and dyspnea at rest or on exertion and had not received any medication in order to control asthmatic symptoms for at least 24 months before the study. Subjects underwent spirometry and methacholine inhalation testing. To be eligible for the study, subjects had to be capable of performing pulmonary function tests in a reproducible way (ie, a coefficient of variation of FEV1 in three consecutive flow-volume curves of < 5%) and needed to have an FEV1 >= 70% of the predicted value.20 Clinical data were obtained retrospectively by reviewing the files of the outpatient clinic.

Both natural parents of the adolescents were asked if they would participate in the study. After obtaining consent, the parents underwent spirometry and methacholine inhalation testing. Testing was performed by a single investigator who had no knowledge of the test results of the children. Parents with a diagnosis of asthma were included in the study. Excluded were the parents with an FEV1 < 70% of the predicted value.21

FEV1 was recorded as the best of three attempts using a computerized spirometer (Microspiro HI 298; Chest; Tokyo, Japan), with measurements not varying by > 5% being acceptable. Methacholine inhalation tests were carried out using a modification of the method described by Chai et al.22 At the time of the study, all subjects had been free of acute respiratory tract infections for 4 weeks and were required to stop receiving medications 7 days before the study. In view of the fact that most of the adolescents were sensitized to house dust mites, it was decided to perform the test during the winter season (December to February), when house dust mite numbers are at their lowest and least variable levels in our country.23 Methacholine (Sigma Chemical; St. Louis, MO) at concentrations of 0.075, 0.15, 0.3, 0.625, 1.25, 2.5, 5, 10, and 25 mg/mL was prepared by dilution in buffered saline solution (pH 7.4). A Rosenthal-French dosimeter (Laboratory for Applied Immunology; Baltimore, MD), triggered by a solenoid valve set to remain open for 0.6 s, was used to deliver the aerosol generated from a DeVilbiss 646 nebulizer (DeVilbiss; Somerset, PA) with pressurized air at 20 pounds per square inch. Each subject inhaled five inspiratory capacity breaths of buffered saline solution, and the study was continued only if the postsaline solution FEV1 was at least 70% of the predicted value.20 21 Increasing concentrations of methacholine were then inhaled until the FEV1 fell by > 20% of its postsaline solution value or the highest concentration was reached. The largest value of triplicate FEV1 at 1.5 min after each inhalation was adopted for analysis. The percentage fall of FEV1 from the postsaline solution value was plotted against log concentration of inhaled methacholine. PC20 was calculated by interpolation between two adjacent data points if the FEV1 fell by > 20%. As not all subjects experienced a 20% drop in FEV1 after inhalation up to the highest concentration of methacholine (25 mg/mL), thereby making PC20 calculation impossible, a continuous index of methacholine responsiveness was required for the entire sample. For this purpose, the log of the slope of the percentage decline from baseline FEV1 after the last concentration of methacholine, per unit concentration of methacholine (bronchial responsiveness [BR] index), was calculated for all the subjects, as described by Burrows et al.24

Parents gave written informed consent for their children and themselves to participate in the study. The study protocol was approved by the hospital ethics committee.

Statistical Analysis
Subjects were considered to have BHR if they had a PC20 < 18 mg/mL. Values for PC20 were logarithmically transformed before analysis, and were expressed as a geometric mean and range of 1 SD. Other values were presented as mean ± 1 SD. Values or frequencies between the two groups of adolescents or of parents were compared using the Student t test or the {chi}2 test, respectively. In each case, statistical significance was accepted when the two-sided p values were < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
One hundred thirty-three adolescents with asthma remission, who had both natural parents, were enrolled in this study. Of the parents, three pairs of parents themselves declined to participate in the study, and one member of four pairs could not perform the test due to a poor technique of forced expiratory maneuver or due to a lower FEV1 level. Complete data were therefore available for 126 adolescents and their parents (Table 1 ).


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  		Table 1. Characteristics of Adolescents and Their Parents Completing the Study*

 
The clinical characteristics of the BHR-positive and BHR-negative adolescents were compared in Table 2 . No differences were observed between BHR-positive and BHR-negative adolescents, with respect to age, sex, age of asthma onset, history of prophylactic medications, duration of asthma remission, atopic status as assessed by total serum IgE and the pattern of positive skin responses, environmental factors, or the FEV1.


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  		Table 2. Clinical Characteristics of BHR-Positive and BHR-Negative Adolescents*

 
Comparison of BR in Parents Categorized by the Presence or Absence of Persisting BHR in Adolescents
Figure 1 compares the BR index and the frequency of BHR between the parents of BHR-positive adolescents and the parents of BHR- negative adolescents. The parents (n = 138) of the BHR-positive adolescents had a BR index of 1.150 ± 0.103 (fathers, 1.144 ± 0.100; mothers, 1.156 ± 0.106). This was statistically different (p = 0.029) from the value (1.124 ± 0.088) [fathers, 1.117 ± 0.091; mothers, 1.131 ± 0.086] obtained from the parents (n = 114) of the BHR-negative adolescents. The frequency of BHR in the parents of the BHR-positive adolescents was 28.3% (39 of 138 parents) [18 of 69 fathers; 21 of 69 mothers], compared to 16.7% (19 of 114 parents) [9 of 57 fathers; 10 of 57 mothers] in the parents of the BHR-negative adolescents (p = 0.030).



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  		Figure 1. Comparisons of the BR index and the frequency of BHR between parents of BHR-positive (BHR[+]) adolescents and parents of BHR-negative (BHR[-]) adolescents. Means ± 1 SD are shown by horizontal bars.

 
Comparison of BR in Adolescents Categorized by the Presence or Absence of BHR in Parents
Figure 2 shows the PC20 and the BR index of adolescents categorized on the basis of whether or not their parents have BHR. Two adolescents had both BHR-positive parents, 54 had one BHR-positive parent, and 70 had both BHR-negative parents. Thirteen of 56 adolescents with at least one BHR-positive parent and 33 of 70 adolescents with BHR-negative parents had immeasurable PC20 (> 25 mg/mL). Excluding these adolescents, PC20 was nevertheless lower in the adolescents of BHR-positive parents than in the adolescents of BHR-negative parents (4.93 mg/mL [range of 1 SD, 1.88 to 12.94 mg/mL] vs 7.78 mg/mL [3.74 to 16.18 mg/mL]; p = 0.030), despite the almost certain underestimation of the difference between these two groups resulting from the above exclusion. Thirty-seven adolescents (66.1%) of BHR-positive parents had BHR, compared to 32 adolescents (45.7%) of BHR-negative parents (p = 0.023). The BR index was also significantly higher for adolescents of BHR-positive parents than for adolescents of BHR-negative parents (1.244 ± 0.090 vs 1.204 ± 0.082, p = 0.011).



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  		Figure 2. Comparisons of PC20 (left panel) and BR index (right panel) between adolescents with at least one BHR parent and those with non-BHR parents. Means ± 1 SD are shown by horizontal bars. Closed circles indicate adolescents with BHR; open circles indicate adolescents without BHR. See Figure 1 legend for expansion of abbreviations.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, over one half of the adolescents with long-term asthma remission had BHR. The parents of adolescents with BHR were found to have a higher frequency of BHR and a greater degree of BR than the parents of adolescents without BHR. Furthermore, adolescents with at least one BHR parent had a higher prevalence of BHR and higher BR index than adolescents with non-BHR parents.

Several previous studies have evaluated the frequency of BHR in patients with asthma who had reached clinically defined remission. Godden et al25 investigated the outcome of childhood asthma after 25 years and found BHR in 42% of the asymptomatic patients. Boulet et al5 demonstrated that 63% of symptom-free and medication-free adults with a history of asthma had BHR. Two further studies26 27 re-examined pediatric asthma patients in adulthood and found BHR in 20% of the asymptomatic patients. Among a group of pediatric and adolescent patients with asthma who became asymptomatic, 41% showed persisting BHR by cold air challenge.6 In the present study, the frequency of BHR was found to be 54.8% (69 of 126 patients). This frequency cannot be compared directly to the results of the above-quoted studies because of the substantial differences in the definition of clinical remission, in the recruitment of subjects, in the challenge methods used, and in the criteria of BHR. In the present study, subjects were regarded to be in clinical remission when they reported complete absence of symptoms and had received no treatment for at least 2 years preceding the study. The relatively high frequency of BHR found in our study might, at least in part, be explained by the selection of subjects from a specialized allergy clinic, which may have been biased toward the more severe end of the asthma spectrum. We previously found that a PC20 > 18 mg/mL virtually rules out current symptomatic asthma28 ; for this reason, this concentration was chosen as a cutoff for clinically relevant BHR for this report.

We examined various asthma features that we believed might be important for predicting the persistence of BHR. Atopy has been found in population studies to be associated with an increase in bronchial responsiveness29 and can heighten BHR when this is already present.30 Gruber et al6 showed that among symptom-free pediatric and adolescent asthma patients, the prevalence of BHR was significantly higher in atopic subjects than in nonatopic subjects. In order to avoid the confounding effect of atopy on the persistence of BHR, only atopic subjects were selected in the present study. There was no difference in total serum IgE levels or positive skin response patterns to aeroallergen between the BHR-positive and BHR-negative adolescents. This suggests that the presence or absence of BHR in adolescents with asthma remission might not depend on their atopic profile. There is evidence to suggest that asthma acts through a chronic inflammatory process, with an increased airway wall thickness and hypertrophy of airway smooth muscle.31 BHR may be the result of such airway remodeling, and several studies32 33 have reported a correlation between the thickness of basement membrane and airway responsiveness in adult asthmatics. Although we cannot estimate to what extent airway remodeling might have contributed to BHR in our subjects, this factor is unlikely to have a major role in the persistence of BHR, since the durations of asthma symptoms or remission and the history of prophylactic therapy were similar for the BHR-positive and BHR-negative adolescent groups.

Studies in both humans and animals have demonstrated a genetic predisposition to BHR,14 34 such as greater concordance for this trait among monozygotic than dizygotic twins.35 Family studies36 37 have also shown that there is a higher frequency of BHR among the relatives of asthmatic subjects than among those of nonasthmatic subjects. To our knowledge, this is the first study in which BR has been assessed in families of adolescents with asthma remission. In addition to examining BR in terms of PC20, we calculated an index of FEV1 decline during methacholine challenge. This method of expressing responsiveness, the BR index,24 provides a continuous variable for BR even in subjects who are not responsive enough to have a measurable PC20. Our results have shown that the BR index and the frequency of BHR were higher in parents of the BHR-positive adolescent group than in parents of the BHR-negative adolescent group. These observations suggest that BHR among adolescents with asthma remission depends on the degree of BR of their parents.

The above findings were substantiated by comparing the frequency of BHR or the BR index between two groups of adolescents categorized according to whether or not their parents had BHR. Adolescents of BHR-positive parents had BHR more frequently and a higher BR index than adolescents of BHR-negative parents. These observations suggest that adolescents in asthma remission are more likely to have BHR when there is a family history of BHR.

Our results may furnish some insights into the mechanism underlying the BHR of adolescents in asthma remission. The demonstration of a familial basis for persistent BHR may provide a piece of evidence that genetic factors may play a role in the BHR of adolescents in asthma remission. It could be argued that persistent BHR in adolescents in combination with a high degree of BR in their parents may be due to their sharing a common "allergic" environment.38 Presumably, adolescents with BHR may have sustained airway inflammation, provoked by an ongoing environmental trigger, which may have also an impact on parental degree of airway responsiveness. In the present study, although the environmental factors were not different between the compared groups with respect to tobacco smoke, pets in the house, or residence location, we cannot rule out the possibility that other unexplored environmental factors may have contributed to our finding. Nonetheless, we believe that our results provide valuable circumstantial information concerning the possible involvement of genetic factors in the BHR of adolescents in asthma remission.

In conclusion, our results indicate that family BHR history may contribute to the persistence of BHR in asthma remission during adolescence. Although this finding may provide a piece of evidence for involvement of genetic influence in BHR of this clinical setting, further studies, including measurements of airway inflammation, are warranted to verify this conclusion.


   Footnotes
 
Abbreviations: BHR = bronchial hyperresponsiveness; BR = bronchial responsiveness; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1

This study was supported in part by Seoul National University Foundation and by BK 21 Human Life Science, Seoul National University.

Received for publication December 9, 2002. Accepted for publication March 26, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Y. Yoo, J. Yu, D. K. Kim, and Y. Y. Koh
Percentage Fall in FVC at the Provocative Concentration of Methacholine Causing a 20% Fall in FEV1 in Symptomatic Asthma and Clinical Remission During Adolescence.
Chest, February 1, 2006; 129(2): 272 - 277.
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