The distribution of bronchial responsiveness to histamine and exercise in 527 children and adolescents

Vibeke Backer, MD,* Asger Dirksen, MD, PhD,** Niels Bach-Mortensen, MD,*** Karen Kaae Hansen,****

Eva Mosfeldt Laursen,**** and Dorthe Wendelboe**** Copenhagen, Denmark

The aim of the study was to describe the bronchial responsiveness to inhaled histamine and exercise in a randomly selected group of 527 children and adolescents from Copenhagen, aged between 7 to 16 years. The distribution of the bronchial responsiveness was described as (I) the provoking concentration that causes a 20% reduction in FEV,, (2) the dose-response slope (DRS), that is, the linear slope of the dose-response curve, and (3) reduction in FEV, after 6 minutes of exercise on a treadmill. The distribution of the concentration that causes a 20% reduction in FEV, in the responsive range was not significantly dt&Gerentfrom a unimodal distribution, although the findings were skewed toward the less responsive end of the range (p > 0.05). The subjects with asthma represented a subgroup within the responsive distribution tail rather than a separate distribution peak. In asymptomatic individuals, the values of DRS were distributed symmetrically on a logarithmic scale. The deviation from normal was such that the standard deviation only slightly underestimated the “normal” range. The distribution of the bronchial response to exercise was found to be significantly different from a normal distribution. However, a significant relationship was found between the bronchial response to inhaled histamine and exercise (p < 0.0001). We conclude that there is a log-normal distribution of the bronchial response to inhaled histamine in a random sample of children and adolescents. (J ALLERGY CLINIMMUNOL 1991;88:68-76.)

Key words: Bronchial responsiveness, distribution, histamine challenge, exercise, children

Measurement of bronchial responsiveness is a widely used approach for assessment of airway vari- ability in children,le3 and BHR is a characteristic fea- ture in asthma,4 although not entirely restricted to children with asthma. Is3 Various factors are of impor- tance for the distribution of bronchial responsiveness

Abbreviations used BHR: Bronchial hyperresponsiveness SFT: Skin prick test PC,,: Provocative concentration causing a 20% fall

in PEV, DRS: Dose-response slope BRE: Bronchial response to exercise

From the *Department of Internal Medicine B, Laboratory of Respiratory Physiology; ***Department of Pediatrics GGK; **Department of Internal Medicine ‘PTA Allergy Unit; and ****Laboratory of Respiratory Physiology, State University Hos- pital, Rigshospitalet, Copenhagen, Denmark.

Supported by the Danish Asthma and Allergy Foundation, the Health Foundation, Pharmacia Copenhagen, Bayer Denmark, the Christian X Foundation, and the Foundation of Mr. C. 0. Hansen and wife (tree Kruse).

Received for publication May 7, 1990. Revised March 11, 1991. Accepted for publication March 13, 199 1. Reprint requests: Vibeke Backer, MD, Jagtvej 200, DK-2100 Co-

penhagen, Denmark. l/1/29413

68

among children,4 such as prevalence of asthma among children,’ frequency of allergic symptoms in child- hood,5 and change of the degree of bronchial respon- siveness with increasing age.‘j Yet, the distribution of the bronchial response to inhaled agents is found to exhibit a unimodal distribution in unselected groups of subjects.7-9 A distribution of bronchial responsive- ness with one peak and with the subjects with asthma situated in the hyperresponsive tail of the curve sug- gests that BHR is a heterogeneous disorder that could

VOLUME 88 NUMBER 1

Bronchial responsiveness in children 69

be caused by both polygenic and environmental fac- tors.7 At the present time, there are data concerning the distribution of the bronchial response to inhaled agents, ‘. 7. 9. ‘O but little information is available about the distribution of the bronchial response, in popu- lation samples, to other stimuli, such as exercise. ” A unimodal distribution of the BRE would support the theory that the distinction between asymptomatic BHR and asthma is arbitrary.

Earlier studies have demonstrated that the bronchial responses to different stimuli among subjects with asthma are closely related to each other.‘*-“’ It is un- known, however, whether such relation exists among individuals without asthma. A close relation between the bronchial responses to different stimuli in subjects without asthma would support a close relationship between nonasthmatic and asthmatic BHR. Further- more, previous studies”, ” have found that bronchial responsiveness to inhaled agents, such as methacho- line, is decreasing during childhood in individuals without asthma.6 If a relationship between the bron- chial response to each stimuli exists, the BRE could follow the same pattern. However, further investiga- tion is needed.

The aim of this study was to determine the distri- bution of bronchial response to inhaled histamine and BRE in a randomly selected group of children and adolescents. The aim was also to investigate a poten- tial relationship between different provocative stimuli in a random sample of children and adolescents.

MATERIAL AND METHODS Subjects

A random sample of 983 children and adolescents living in the area surrounding the State University Hospital of Copenhagen was drawn from the civil registration list and invited to participate in the study. All subjects who were invited were born in the first week of each month, all sub- jects were aged between 7 to 16 years, and all were white subjects. Five hundred twenty-seven subjects (53.6%) ac- cepted the invitation and were examined. Two hundred sixty-two were boys and 265 were girls; median age was 12 years. A sample of 100 nonresponders (families who did not respond when they were contacted by letter) was con- tacted by telephone. The families of these nonresponding children answered the same questionnaire as the visiting children. There was no difference in sex, age, or disposition to allergic symptoms between responders and nonrespond- ers, but there were significantly fewer children with allergic symptoms in the group of nonresponders (Table I). All par- ticipants and their parents were interviewed by one of the authors (V. B .) and filled in a questionnaire about asthmatic symptoms” and other allergic symptoms, that is, rhinitis (sneezing, running, or blocked nose not associated with a cold) and eczema (an itchy dry rash on face, arms, or legs), as related to themselves, their siblings, and their parents.’

TABLE I. Five hundred twenty-seven responders and a sample of 100 nonresponders by allergic symptoms (allergy), family background of allergic diseases in first degree relatives (background), sex, and age

Responders Nonresponders (N = 527) (N = 100)

Allergy Background Sex

F M

Age W (mean)

111* 12 205 32

265 42 262 58

12.0 13.0

Informations were obtained by interview in the clinic (responders) or by telephone (nonresponders).

*Chi-square, p < 0.05.

The material (527 individuals) was divided into two groups. The criteria for diagnosis of asthma used in this investigation are in accordance with the method of Hopp et al. Is The questions were as follows: (1) Have you ever had asthma diagnosed? (2) Have you ever had wheezy or dry cough? (3) Do you have attacks of shortness of breath with wheezing? (4) Have you ever been hospitalized and/or been treated for asthma by a doctor? (5) Have you ever received medication for your asthma? (6) Did the med- ication help? (7) Does exertion, stress, cold air, damp weather, or allergen exposure cause pulmonary symptoms (Table II)?

Group 1: children and adolescents with asthma (N = 28). Twenty-eight subjects fulfilled the criteria for having bronchial asthma.15 Twenty children had definite asthma, that is, positive response to questions 1 through 6. None had probable asthma, that is, positive response to questions 1, 2, 3, 4, and 5 or 6, whereas eight children had ques- tionable asthmatic symptoms, that is, positive response to any two of questions, I, 2, 3 and any one of questions 4 through 7. All the individuals with asthma had present symptoms. Twenty-three subjects had continuous asthmatic symptoms, whereas three subjects only had seasonal symp- toms. Nineteen of the 28 subjects with asthma had a positive SPT, and nine subjects had a negative WT. All the children with asthma and adolescents underwent the histamine- challenge tests, and 26 of 28 subjects with asthma had the exercise test performed.

Group 2: children and adolescents without asthma (N = 499). Among the subjects without asthma, allergic diseases were found in 92, rhinitis in 43, rhinitis and/or eczema in 35 subjects, and asymptomatic positive SFT in 14 subjects. In cases of known seasonal allergy, the chal- lenge tests were performed out of season. Twenty-two sub- jects with either rhinitis or eczema had at least one positive WT. Eighty-two subjects (16%) claimed doubtful respira- tory symptoms, whereas 417 individuals had no respiratory

70 Backer et al.

Number of subiects

J. ALLERGY CLIN. IMMUNOL. JULY 1991

50

40

30

20

10

0 0.2 0.5 1.0 2.0 4.0 8.0 PC20 (mg/ml histamine)

FIG. 1. Subjects with BHR to histamine, defined as PCx, ~8.0 mglml. Black area represents the subjects with asthma; striped area represents the subjects without asthma with respiratory symptoms; open bars are the individuals without asthma with no respiratory symptoms.

TABLE II. Results of the questionnaire about pulmonary symptoms (questions 1 through 7) in the two groups of subjects

Have you ever had?

Wheeze or dry Shortness of Asthma Exercise-induced Asthma cough breath medication asthma

Total No. of Question No. 1 2 3 4-6 7 subjects

With asthma 20 28 28 20 28 28 Without asthma 0 76* 6 0 0 499 Total 17 86 33 17 28 527

*Seventy-five subjects (99%) only claimed dry cough.

symptoms at all (Table II). Seventy-five of the 82 subjects had occasional cough, six had experienced shortness of breath, and one subject had experienced wheezing on one occasion. A family history of atopic diseases was found in 183 (37%) of the subjects.

Methods All subjects were asked not to smoke for 2 hours before

their appointment. Subjects were to avoid taking theoph- yllines or antihistamines for at least 24 hours (astemizole for 6 weeks), oral B-agonist for 18 hours, and inhaled bron- chodilators for 6 hours before testing. Inhaled steroids were continued, if they were used, with no limitation. In case of recent respiratory infection, challenge tests were postponed for at least 6 weeks.

subjects were performed. Both tests were performed in 464 (88%) of the participants. Five subjects were excluded be- cause of systemic diseases, one had cancer treated with chemotherapy, two were epileptic, and two subjects were mentally deficient. One subject had an FEV, cl.0 L and was excluded. Twenty-six subjects (5%) refused to continue the histamine-challenge test after inhalation of saline or were unable to perform technically satisfactory FEV, maneuvers. Twenty-eight adolescents, mostly female teenagers, were unable to complete the exercise test after a few minutes of running because of self-consciousness in the clinical situ- ation or poor physical fitness. None of these subjects ex- perienced a reduction in FEV, after having stopped the test.

Lung function A baseline lung function and baseline parameters were A baseline FEV, and FVC were measured with a dry

measured (Table III). Additionally, an exercise test in 494 spirometer (Vitalograph, Vitalograph Ltd., Buckingham, (94%) subjects and a histamine challenge test in 495 (94%) England). Peak expiratory flow rate was measured with a

VOLUME 88 NUMBER 1

Bronchial responsiveness in children 71

Number of subjects

FIG. 2. Cumulated DRS in 495 unselected individuals. Black area represents the children with asthma; striped area represents the subjects without asthma with respiratory symptoms; open bars are the individuals without asthma with no respiratory symptoms.

TABLE III. Age, height (centimeters), basic lung function parameters, log DRS, and percentage of BRE in 527 children and adolescents

Total (N = 527) With asthma Without asthma

(N = 28) (N=488)

Age (yr) 12.0 (10-14) 12.0 (10-15) 12.0 (10-14) Height 155.0 (140-165) 154.0 (143-163) 155.0 (140-165) FEV, 2.4 (1.8-3.1) 2.3 (1.7-2.6) 2.4 (1.8-3.1) FEV, % pred 96.1 (89-105) 88.7 (78-103) 96.3 (90-105) Percent 90.0 (86-93) 90.5 (87-94) 90.0 (86-93)

FEv,/vc DRS 0.2 (0.2-0.3) 0.6 (0.5-1.2) 0.2 (0.1-0.2) BRE 4.0 (2.0-7.3) 15.5 (8-27) 4.0 (2-7)

% pred, Percent predicted. Figures in median (and interquartiles).

mini-Wright peak flow meter. The best of three technically acceptable measurements was recorded. Predicted values based on the height of the subjects were calculated in ac- cordance with the method of Zapletal et al.16

Bronchial histamine-challenge test

Histamine-challenge tests were performed according to the method of Cockcroft et al.” All tests were performed between 2 PM and 5 PM. The histamine was delivered by a Wright nebulizer with an output of 0.14 X lo-’ t 0.015 L/min, with a pressure of 182 kPa and a flow of 10 L/min. The subjects were instructed to inhale by normal tidal vol- ume breathing and were continuously supervised. Nine con- centrations of freshly made solutions of histamine were used: 0 (saline) to 8.0 mg/ml, starting with the lowest

concentration and terminated when the maximum concen- tration had been reached, or when PC,, was observed. The threshold value of BHR was PC, of 8 mg/ml. The per- centage reduction in FEV, per micromoles of the last inhaled concentration of histamine, that is, the DRS, was recorded and used in the analysis.‘* The DRS was calculated in both a noncumulative and a cumulative manner. Before expres- sion in log scale, 1.2% decline in PEV, per micromoles was added to each value to eliminate negative and zero values. ‘*

Exercise test The exercise test consisted of steady running on a 10%

sloping treadmill for 6 minutes.19 The speed was adjusted to maintain the heart rate between 160 to 180 beatslmin. The ambient air temperature and relative humidity were kept

72 Backer et al. J. ALLERGY CLIN. IMMUNOL.

JULY 1991

Number of subjects 1601

120

80

60

-12 -8 -4 0 4 8 12 16 20 24 28 32 36 40

BRE

FIG. 3. BRE in 494 unselected individuals. B/a&area represents the children with asthma; striped area represents the subjects without asthma with respiratory symptoms; open bars are the individuals without asthma with no respiratory symptoms.

constant at 21” C and at 40% to 50%, respectively. The FEV, was measured before the test, immediately after (time 0), and after 1, 3, 5, 10, and 15 minutes. The highest of three FEV, readings was used for analysis. The maximum BRE, that is, the maximal change in FEV, within 15 minutes after exercise, was recorded, and the results were calculated as the percentage change in FEV, from the maximal preex- ercise values. I2

Ethics and statistical analysis

The protocol was evaluated and approved by the local ethical committee, and all subjects participated according to informed consent. The Helsinki II declaration was ad- hered to throughout the study.

The population distribution curve of the variables, FY&, log DRS, BRE, and log BRE, was analyzed with the Kolmogorov-Smimov, one-sample test for goodness of fit. The association between respiratory symptoms and bron- chial responsiveness was analyzed by chi-square test. The change in bronchial responsiveness to both inhaled hista- mine and exercise with age was analyzed with a univariat regression analysis. Finally, the correlation between DRS and cumulated DRS, and DRS and BRE was analyzed with a Spearman’s rank-correlation test. A two-tailed significance level of the type I error was fixed at 5%.

RESULTS

Baseline FEV, percent predicted values for all sub- jects are presented in Table III. Baseline FEV, values were significantly lower in the subjects with asthma (median FEV,, 97.6 percent predicted) than in the subjects without asthma (median FEV,, 105.8 percent

predicted) (p = 0.03). There were no significant dif- ferences between subjects with or without asthma re- garding peak expiratory flow and FVC (p > 0.05; data not presented). We found that the noncumulated DRS was almost perfectly correlated with the cu- mulated DRS, since a correlation coefficient of r = 0.96 was found (p < 0.001).

The population distribution of PC& (Fig. l), log DRS (Fig. 2), and BRE (Fig. 3) all appear to exhibit an unimodal di&ibution. However, only the distri- bution of PC2,, could not be differentiated at the 5% level from a unimodal normal distribution with the Kolmogorov-Smimov, one-sample test (Table IV). The DRS value for 1.96 SD below the mean in the asymptomatic group is 9.2% reduction of FEV, per micromolars indicating a slight overestimation of the criteria for abnormality (Fig. 4). No such over- estimation regarding BRE was found among the 391 asymptomatic individuals.

In the group of subjects without asthma, decreasing bronchial response to inhaled histamine with increas- ing age was demonstrated (Fig. 5; p < 0.001). Like- wise, a decreasing BRE with increasing age was found (Fig. 6; p = 0.01). No such relationship was found among the subjects with asthma (data not pre- sented).

The correlation between the log DRS and the log BRE among subjects with asthma was definite (r = 0.96;~ < O.OOl), whereas the same correlation among children and adolescents without asthma was

VOLUME 88 NUMBER 1

Bronchial responsiveness ;n children 73

260 rmber of subjects i

1.0 10 100 400

DRS

FIG. 4. Cumulated DRS in 417 individuals without asthma. Swiped area represents the subjects with respiratory symptoms; open bars are the individuals with no respiratory symptoms.

TABLE IV. Analysis of the distribution of histamine-challenge test and exercise-induced bronchocontriction in children and adolescents, aged 7 to 16 years

Topics No. of subjects Kolmogorov-Smirnor P

PC& all* 495 0.478 PC, C8.0 mg/ml 79 0.115 Log DRS (noncumulated) 495 0.235 Log DRS (cumulated) 495 0.162 Log DRS (asymptomatic) 391 0.137 BRE 494 0.223 BRE (asymptomatic) 391 0.143 Log BRE 494 0.180

*Nonresponsive subjects with PCm > 8 mglml were calculated as PC,,, 16 mglml.

<o.ooo CO.245 (NS) <o.ooo a.ooo <O.OOl a.ooo <O.OOl a.ocm

highly significant, although the correlation was rather poor (r = 0.23; p < 0.0001).

Furthermore, a close association between severe bronchial responsiveness and respiratory symptoms in both allergic subjects and subjects with asthma was found (Table V; p < 0.001).

DISCUSSION

From a theoretical point of view, a multimodal dis- tribution of characteristics, mainly under genetic con- trol, might be expected, whereas characteristics under both genetic and environmental control have a uni- modal distribution. However, epidemiologic studies of characteristics, such as blood pressure or phar- macologic reversibility of air-flow obstruction, have always demonstrated a unimodal distribution rather

than a multimodal distribution, making the distinction between disease and health arbitrary. Even though the distributions are found to be unimodal. they are often skewed toward one of the tails. We found that the distribution of P&, that is, histamine threshold values in the responsive range, had a unimodal distribution, which is in accordance with BHR being under both genetic and environmental control. This finding is in accordance with other studies.‘, ‘, ’ When the distri- bution of BHR is being examined, groups of children and adolescents are quite unique, compared with adult studies, because of less confounding factors that could alter the distribution of subjects with HHR.4. I’, ‘O Un- like adults, children seldom have diseases that affect the degree of responsiveness. Irreversible obstructive lung diseases2’ and the number of smokers,22 known

74 Backer et al. J. ALLERGY CLIN. IMMUNOL. JULY 1991

0,25

02

0,15

OS1

0,05

0

DRS 0,3 -

I I I I I t 1 I I 1

7 8 9 10 11 12 13 14 15 18

Age in years (non-asthmatic)

FIG. 5. Relationship between the cumulated DRS and age of 495 children and adolescents.

to alter the percentage of individuals who have BHR, are almost zero among children.

The major advantage of DRS, compared to P&,, is that a value can be calculated for the entire popu- lation, including the individuals who were censored when PCzO values are used. The ability to calculate DRS values for tbe entire population may overcome some of the problems encountered in longitudinal pop- ulation studies of BHR. Although DRS, calculated as a slope + 1.2, did not have an absolutely normal distribution, its distribution was symmetrical, and thus, the mean was a reliable measure of its central position. The deviation from normal was such that the standard deviation only slightly underestimated the “normal” range. The distribution appears to be close enough to normal to warrant the use of parametric summary statistics. A unimodal distribution of DRS is in accordance with other investigators.“” ‘O. I8 When groups of children are studied, various factors, like growth and recent respiratory infections, could alter the distribution of bronchial response. However, none of the children examined in the study claimed recent respiratory infections, whereas the slight distinction from a unimodal distribution might be because of a smaller number of individuals in the present study, younger participants, increased number of age groups, or a minor participation frequency, compared with, for example, the study by Cockcroft et al.’ and Salome et al.,’ who, in an increased number of participants and a reduced number of age groups, found a uni- modal distribution of PDm. However, future follow-

up studies of children with asymptomatic BHR will probably reveal whether the distinction between BHR with asthma and BHR without asthma remain arbi- trary, both in subjects with BHR and subjects without.

Many children (Fig. 2) did not react at all to ex- ercise, a few reacted strongly, and a significant num- ber of children demonstrated intermediate bronchial responsiveness without experiencing asthma or asth- matic symptoms. Thus, the distribution of BRE is, to some extent, different from the distribution of the bronchial response to inhaled histamine. However, there are important technical differences in the two challenge tests that could explain this difference. The exercise test is based on a single-dose challenge, whereas histamine-inhalation tests imply multiple doses of increasing strength, which could explain the difference in distribution between the two tests.

Previous studies’O* I’ have found that bronchial re- sponsiveness to inhaled methacholine is dependent on age. Our data support the suggestion that not only does responsiveness to methacholine decrease with age but also responsiveness to other nonspecific stim- uli, such as exercise and histamine. This study could not solve the problem of whether subjects with asthma during growth from childhood to adulthood have an overall loss of, or substantial improvement in, BHR. Such a finding would have been in agreement with the evolution of asthma during childhood.g However, in subjects without asthma, it appears as though a general decrease in bronchial responsiveness occurs

VOLUME 88 NUMBER 1

Bronchial responsiveness in children 75

BRE 121

8-

OL ’ I I I I + -I- I A-

7 8 9 10 11 12 13 14 15 18

Age in years (non-asthmatic)

FIG. 6. Relationship between 8RE and age of 494 children and adolescents.

TABLE V. Relationship between respiratory symptoms, that is, no respiratory symptoms, doubtful asthma, and certain asthma, and bronchial responsiveness to either histamine or exercise in randomly selected children and adolescents

Asymptomatic Doubtful asthma Certain asthma (N = 391) (N = 62) (N = 28)

&l Mean 18.0 >8.0 3.07* 1 SD 3.51 4.39 3.34

DRS Mean 1.55 7.21 29.70* 1 SD 0.65 46.50 80.90

BRE Mean 4.14 4.93 15.39* 1 SD 5.83 5.93 13.75

*p < 0.001.

as the subjects grow older.6* 23 Change in bronchial responsiveness during the life of individuals has been demonstrated in other studies.‘, 9 This change in bron- chial responsiveness during life could be associated with changes in allergic symptoms during growth or changes during life in those environmental factors that may alter bronchial responsiveness.4 Future longitu- dinal examinations of BHR in children are necessary to demonstrate factors that cause a decrease of bron- chial responsiveness during growth.

Exercise as a single stimulus is a less sensitive test than the histamine challenge. There was a poor agree- ment between the two measurements, since only 5% (r = 0.23) of the variation of DRS may be explained

by the response to exercise. The correlation between the different challenge tests was highly significant (p < 0.001)) which can be explained by the large number of nonresponsive children and adolescents in the study. The weak relationship between BRE and inhaled histamine in unselected children and adoles- cents is different from the very close relationship found in subjects with asthma both in this study and in other studies. ‘*-14, 24

Intensified responsiveness was clearly a central fea- ture of asthma, which is in accordance with other studies. ‘. 3 A follow-up of our subjects in the future may reveal whether bronchial hyperrespon- siveness predisposes to the development of asthma.

76 Backer et al.

The fact that some children with hyperresponsiveness develop symptoms of asthma,*’ whereas very few chil- dren without responsiveness are found to develop asthma,” indicates a close relationship between BHR and asthma.

This study indicates that increased BRJZ and bron- chial response to histamine could be different path- ogenetically. However, the bronchial response on in- haled agents and exercise might also represent similar physiologic abnormalities in children and adolescents without asthma, since some relationship between the two stimuli exists.

We thank the laboratory department of respiratory phys- iology for use of equipment, and to the laboratory techni- cian, K. BetIger, who has helped with the two tests.

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