Airway responsiveness and atopy in families of patients with asthma

Catherine Laprise, MSc
Louis-Philippe Boulet, MD

Clin Invest Med 1996; 19 (6): 461-9.

[résumé]

From the Centre de pneumologie de l'Hôpital Laval, Université Laval, Sainte-Foy, Que., and the Réseau canadien des Centres d'excellence en santé respiratoire.

(Original manuscript submitted Jan. 26, 1996; received in revised form June 11, 1996; accepted July 15, 1996)

Paper reprints may be obtained from: Dr. Louis-Philippe Boulet, Hôpital Laval, 2725 ch. Sainte-Foy, Sainte-Foy QC G1V 4G5

Copyright 1996, Canadian Medical Association

Contents

Abstract

 Objective: To determine whether there is an increased prevalence and degree of airway hyperresponsiveness (AHR) and atopy in families of patients with asthma.

Design: Case­control study.

Setting: Asthma clinic and surrounding community.

Patients: A group of 28 families (n = 122) with one member who had attended the asthma clinic and a control group of 28 families (n = 122) from the same community.

Interventions: Each family member completed a questionnaire and underwent expiratory flow measurement, skin prick tests for allergies, methacholine tests and measurement of total serum IgE level and blood eosinophil count.

Outcome measures: Presence of atopy and AHR and relations between asymptomatic AHR or asthma and atopy, serum IgE levels or blood eosinophil counts.

Results: The group of families with a member with asthma had an increased prevalence of atopy and AHR, lower PC20 methacholine and higher serum IgE levels in comparison with controls, even when the first identified family members with asthma and their matched controls were not included. The subjects with atopy in the group with a patient with asthma had higher atopic indices and serum IgE levels than those in the control group, in whom asymptomatic AHR was less closely related to atopy. There was a significant correlation between PC20 methacholine level and atopic index, between blood eosinophil count and serum IgE level, and between atopic index and serum IgE level, for all groups. The proportion of women with asymptomatic AHR was almost twice as high as that of men.

Conclusion: First-degree relatives of subjects with asthma have a higher prevalence of AHR, atopy and elevated serum IgE levels than controls from nonasthmatic families. Subjects with atopy in families of patients with asthma have higher atopic indices and degree of AHR than controls with atopy.

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Résumé

Objectif : Déterminer si la prévalence et le degré d'hyperréactivité bronchique (HVB) et d'atopie sont accrus dans les familles de sujets asthmatiques.

Devis : Étude cas­témoin.

Cadre : Clinique d'asthme et communauté avoisinante.

Sujets : Un groupe de 28 familles (n = 122) dont un membre avait fréquenté la clinique d'asthme, et un groupe-témoin de 28 familles (n = 122) de la même communauté.

Interventions : Chaque membre de la famille a répondu à un questionnaire et subi les analyses suivantes : mesures de débit expiratoire, tests cutanés d'allergie, épreuves à la métacholine et dosage du niveau sérique total d'IgE et du décompte sanguin des éosinophiles.

Variables mesurées : Présence d'atopie et d'HVB; relations entre, d'une part, HVB asymptomatique ou asthme et, d'autre part, atopie, niveau élevé d'IgE sériques ou de décompte sanguin d'éosinophiles.

Résultats : Le groupe de familles avec un membre asthmatique avait une prévalence accrue d'atopie et d'HVB, un résultat plus bas de métacholine CP20 et un niveau sérique d'IgE plus élevé en comparaison avec les témoins, même en excluant les premiers membres de la famille avec asthme et leurs témoins appariés. Dans le groupe avec un asthmatique, les sujets avec atopie avaient des indices d'atopie de même qu'un niveau sérique d'IgE plus élevés que dans le groupe-témoin. Dans ce dernier groupe, l'HVB était moins associée à l'atopie. Pour tous les groupes, une corrélation significative a été observée entre l'index d'atopie et le niveau de métacholine CP20, de même qu'entre l'index atopique et le niveau sanguin d'IgE. Le pourcentage de femmes avec HVB asymptomatique était presque deux fois plus élevé que chez les hommes.

Conclusion : Les apparentés de sujets asthmatiques ont une prévalence plus élevée d'HVB, d'atopie et de niveaux sériques élevés d'IgE en comparaison aux familles non asthmatiques témoins. Dans les familles des asthmatiques, les sujets atopiques ont des indices d'atopie et un degré d'HVB plus élevés que les témoins.

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Introduction

Asthma is a common disease involving airway inflammation. It is characterized by an increased responsiveness of the tracheobronchial tree to stimuli and by episodes of reversible airflow obstruction.[1­3] Various causes of asthma have been suggested, but it is generally attributed to the influence of environmental factors in genetically predisposed people, such as those with atopy.[4,5]

Although airway hyperresponsiveness (AHR) is a common characteristic of symptomatic asthma, it may also be observed in the absence of respiratory symptoms. The prevalence of asymptomatic AHR in the general population is variable; estimates from studies have varied from less than 5% to 50% of the population studied.[6,7] Furthermore, up to 30% of subjects with AHR to histamine report having no symptoms of asthma.[8]

The association between asthma and allergy has been recognized for years. The prevalence of asthma and AHR is higher in patients with atopy than in those without atopy.[2,9­13] Clifford and associates[9] showed a significant association between atopy and AHR to methacholine, independent of symptoms. Furthermore, Pepys[14] suggested an association between atopic status and the risk of asthma in close relatives.

On the other hand, there also seems to be a close relation between high levels of IgE and a family history of atopy.[15] However, some patients with allergy have a normal serum IgE level, and patients without atopy can have high level. A study by Burrows and associates[16] suggests that asthma is mainly associated with a high levels of IgE, whereas rhinitis is mainly associated with atopy. Sears and associates[17] have also shown that AHR to methacholine is related to serum IgE levels, even in children without a diagnosis of asthma.

Most studies of the influence of hereditary factors in asthma and atopy suggest a genetic predisposition, which is probably multifactorial.[18­20] There also seems to be a family concentration of high levels of serum IgE and of response to allergy skin tests.[15] We believed it would be of interest to look at the prevalence of these findings in asymptomatic adults with AHR.

Finally, there is a need to document further the characteristics of patients with asymptomatic AHR and compare the possible determinants of this condition with those associated with asthma in order to identify any similar mechanisms or etiologic factors.

This study documents the comparative prevalence and degree of asthma, atopy and asymptomatic AHR in first-degree relatives of patients with asthma, and compares these findings with those in control families. We also wanted to determine the relations between either symptomatic asthma or asymptomatic AHR and atopy, high levels of IgE or eosinophilia. Finally, we looked at the relative prevalence of sensitivity to various categories of common allergens among the family members with atopy and at the likelihood of asthma, asymptomatic AHR or atopy among patients according to the parents' history of these conditions.

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Methods

Subjects

All subjects were residents of the Quebec City metropolitan area aged 14 to 70 years (mean 33.6, standard error of the mean [SEM] 1.3 years). Patients with asthma were recruited from the asthma clinic at Hôpital Laval, Quebec City. After identification of a patient with asthma, the patient's family was recruited. In total, 28 families comprising 122 subjects were recruited (group A). The controls (subjects without asthma) were drawn from a group (group C) of 28 control families comprising 122 subjects from the same neighbourhood as the case families. The 60 subjects with atopy and the 38 with asymptomatic AHR in group A were compared with 37 and 25 subjects, respectively, in the control group.

The study was approved by our local ethics committee. Patients with asthma were stable at the time of the study; in the previous month they had had no respiratory infections or exacerbations of asthma. All subjects confirmed their willingness to take part in this study and signed an informed-consent form.

Definitions

Asthma was defined according to the criteria suggested by the American Thoracic Society.[1] Asymptomatic AHR was defined as a PC20, the provocative methacholine concentration inducing a 20% fall in forced expiratory volume in 1 second (FEV1), of less than 16 mg/mL, in the absence of symptoms suggestive of asthma (dyspnea, cough, wheezing, phlegm production or chest tightness) in subjects who had never required drug therapy for asthma.[21] Subjects were considered to have atopy if they had at least one positive response to skin prick tests with a battery of common airborne allergens;[22] a positive response was defined as appearance of a wheal with a diameter at least 3 mm 10 minutes after the test.

Evaluation

Each subject completed a general questionnaire on respiratory health, and each subject's family history of asthma or atopy was noted.

Expiratory flows were measured with a Vitalograph PFT II spirometer (Vitalograph Medical Instrumentation, Lenexa, Kan.). The best of three forced-expiratory-volume curves was used to determine the maximal baseline forced vital capacity and FEV1. This procedure was performed according to the recommendations of the American Thoracic Society.[23]

Peak expiratory flow (PEF) was measured with a mini-Wright peak flow meter (Armstrong Medical, Scarborough, Ont.) each morning and evening for 2 weeks. The best of three repeated measurements taken at each time was noted on a diary card.

Subjects underwent skin prick tests with a battery of airborne allergens, which were divided into six main categories: animal dander, dust, house dust mite, tree pollen, grass pollen and moulds. The atopic index was the number of aeroallergen categories (0 to 6) to which the patient showed at least one positive response.

Methacholine inhalation tests were carried out according to the method described by Juniper, Cockcroft and Hargreave.[24] Aerosols were generated by a Wright nebulizer (Roxon Medi-Tech, Montreal, Que.) with an output of 0.13 mL per minute. After the initial control saline inhalation, subjects inhaled, by tidal mouth breathing for 2 minutes, concentrations of methacholine that doubled at intervals of 5 minutes, increasing from 0.03 to 256.00 mg/mL. The percentage fall in FEV1 so caused was measured at 30 and 90 seconds, and then at 2-minute intervals, if necessary.

The determination of serum IgE was performed by immunoenzymofluorometry. Blood eosinophils were counted with a Coulter STKS (Coulter STKS, Hialeah, Fla.).

Statistical analysis

The PC20 and serum IgE level values were log-transformed before analysis. The groups were compared with the exact method of Fisher­Irwin for parametric data. The methacholine PC20 values between groups were compared with Student's t-test for unpaired values. The Wilcoxon­Mann­Whitney test was used to compare the mean values. Correlations were measured with the Spearman correlation coefficient. A p value of 0.05 was considered statistically significant. For statistical analysis, a PC20 greater than 256 mg/mL was considered equivalent to 256 mg/mL.

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Results

Subjects' characteristics

The first identified patients with asthma in group-A families (n = 28) and their age- and sex-matched control subjects in group C were excluded from the calculation of prevalences and pulmonary function variables. The subjects in groups A and C did not differ significantly in regard to sex and age (Table 1). As expected as a result of the exclusion criteria for control families, no subject in group C had symptomatic asthma. FEV1 and variability of PEF were similar in the two groups (Table 1). In addition, in group A, the geometric mean serum IgE level (108.4 µg/L, SEM 1.2 µg/L) was higher than that in group C (58.1 µg/L, SEM 1.2 µg/L) (Table 1).

There was no significant difference in the prevalence of atopy and symptomatic asthma by sex (p > 0.05). There were 63 subjects with asymptomatic AHR. Its prevalence was higher in women (66.1%) than in men (33.9%, p = 0.01) (Table 2). This observation was true in all age categories, except in the subjects aged 50 years and older, among whom the proportion of women and men with AHR was the same (Table 2).

Prevalence of atopy and AHR

There was a significantly greater prevalence of atopy among those in group A than among those in group C (69.6% v. 42.2%, p = 0.0002), and the same was true for AHR (51.1% v. 26.7%, p = 0.0002) and for geometric mean serum IgE levels (108.4, SEM 1.2 µg/L v. 58.1, SEM 1.2 µg/L, p = 0.008, Fig. 1). There were more subjects with asymptomatic AHR in group A than in group C (41.3% v. 26.7%, p = 0.02, Fig. 1). The proportion of subjects with both asymptomatic AHR and atopy was higher in group A than in group C (33.7% v. 13.4%, p = 0.001, Fig. 1). Conversely, the proportion of subjects with asymptomatic AHR but without atopy was lower in group A than in group C (7.6% v. 13.4%, p > 0.05, Fig. 1). The proportion of subjects with neither asymptomatic AHR, asthma nor atopy was therefore higher in group C (22.8% v. 44.4%, p = 0.002,Fig. 1).

Comparison of subjects with atopy and asymptomatic AHR in the two groups

In all, 97 subjects -- 60 in group A and 37 in group C -- had atopy. There were no significant differences in age, FEV1 and variability of PEF between the groups. Mean blood eosinophil counts and geometric mean serum IgE levels were similar in the subjects with atopy in the two groups. Airway responsiveness was greater in the subjects with atopy in group A than in those in group C (PC20 geometric mean 19.01, SEM 1.2 mg/mL v. geometric mean 53.1, SEM 1.3 mg/mL, p = 0.002,Table 1).

Sixty-three subjects -- 38 in group A and 25 in group C -- had asymptomatic AHR. There were no significant differences in age, FEV1, diurnal variability of PEF, PC20 methacholine level and blood eosinophil count between the two groups. Atopic index and serum IgE levels were higher in the subjects with asymptomatic AHR in group A than in those with asymptomatic AHR in group C (mean atopic index 2.8, SEM 0.4 v. 1.4, SEM 0.4, p = 0.01; geometric mean serum IgE level 123.02, SEM 1.36 µg/L v. 63.1 µg/L, SEM 1.4, p = 0.0001, Table 1).

Probability of asymptomatic AHR and atopy according to their parents' history

Table 3 summarizes the likelihood of a subject having asthma, asymptomatic AHR and allergy, according to his or her parents' history of these conditions, in groups A and C. In group A, when both parents had asthma, their offspring had an 83.3% chance of inheriting this condition; when one parent was affected, the likelihood was 40.0%; and when neither parent had asthma, the likelihood was 20.0%. Since the control families had no subjects with asthma, comparable data was not obtained for them. In regard to asymptomatic AHR, when both parents had this condition, their offspring had a 77.8% (group A) and 100.0% (group C) chance of inheriting it; when one parent was affected, the likelihood was 32.0% (group A) and 70.0% (group C); and when neither parent had had asymptomatic AHR, the likelihood was 23.3% (group A) and 28.2% (group C). When both parents had atopy, their offspring had a 79.0% (group A) and 88.9% (group C) chance of inheriting it; when one parent was affected, the likelihood was 77.8% (group A) and 53.3% (group C); and if neither parent had it, the likelihood was 53.3% (group A) and 30.8% (group C).

Correlations between serum IgE level, PC20 methacholine level and eosinophil count

Table 4 shows the correlations between the serum IgE level and (1) PC20 methacholine levels, (2) eosinophil counts and (3) atopic index in each group, in the subjects with atopy in each of the two groups and in the subjects with asymptomatic AHR in each of the two groups. There was a negative correlation between the serum IgE level and the PC20 methacholine level in all groups. There was a significant and positive correlation between the serum IgE level and eosinophil count in group A, group C, the subjects with atopy in group A and the subjects with asymptomatic AHR in group A and in group C. There was also a positive correlation between the serum IgE level and the atopic index in all groups.

Sensitivity to common allergens

The prevalence of atopy was higher in the children whose parents had a history of atopy than in the subjects whose parents did not have such a history (Table 3). Table 5 shows the proportion of offspring with atopy associated with their parents' history of atopy for the various categories of allergens.

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Discussion

The prevalence of AHR, atopy and elevated serum IgE levels was higher in the first-degree relatives of the subjects with asthma than in relatives of the matched controls, but, most importantly, the subjects with atopy in the case group had a higher atopic index and degree of AHR than those with atopy in the control group. Furthermore, asymptomatic AHR was more common in group A, and the subjects in this group had a higher mean atopic index and geometric mean serum IgE level than those with asymptomatic AHR in group C. For subjects in both groups, there was a correlation between serum IgE level and blood eosinophil count, between PC20 methacholine level and atopic index, and between atopic index and serum IgE level.

Some of our results are in keeping with previous observations.[5,21,25] However, we also showed that, in the subjects with atopy in families with a member with asthma, compared with control families, the prevalence of AHR and atopic indices were higher, suggesting a genetic tendency to develop a high degree of atopy, although similar environmental exposures to allergens could also be involved. Furthermore, the subjects with asymptomatic AHR from the case families also had higher atopic indices and IgE levels than those with asymptomatic AHR from the control families. The degree of airway responsiveness was correlated with atopic index, and atopic index with serum IgE level.

When the first family member with asthma identified was excluded from our analysis, the incidence of asthma observed in the case group was 9.4%. Studies in Arizona and New Zealand have shown a prevalence of asthma of 5% to 10.6% among populations of children.[2,3] Woolcock, Colman and Jones[26] showed a prevalence of atopy of 40% to 55% in general and military populations, respectively, whereas the prevalence was 42% in a group of municipal parkworkers and control subjects studied by Desjardins and associates[27] and 43.8% in a cohort of children in a study by Sears and associates.[3] These results are somewhat similar to those of our study, although the prevalence we found was higher in group A than in group C.

Cockcroft, Murdock and Bercheid[6] have suggested that methacholine responsiveness has a unimodal distribution in a random population. Townley and associates[28] have, however, reported a bimodal distribution of methacholine responsiveness in first-degree relatives of people with asthma. These observations are similar to our results for the distribution of PC20 methacholine levels in families with a member with asthma.

In the study by Sears and associates,[3] atopy was significantly more common in boys than in girls, and asthma was also more common in boys. On the other hand, Barbee and associates,[29] as in our study, did not show any difference between sexes in the frequency of atopy and asthma. We found, however, a higher prevalence of asymptomatic AHR among women; this phenomenon was not associated with age or atopic status and may be associated with another factor, such as airway calibre.[30,31]

Our data show that AHR was twice as common among the subjects with atopy than among those without it (p = 0.001). Similarly, Pattermore and associates[32] showed that 50% of the subjects with AHR had atopy, compared with 33% of the subjects without AHR. In a student population, Clifford and associates[9] found a significant association between atopy and bronchial hyperresponsiveness to methacholine, independent of symptoms. Our findings also show a correlation between these variables.

When we compared the subjects with atopy in group A with those in group C, we noted a larger proportion of subjects with AHR in subjects with atopy from group-A families. According to our data, AHR and atopy are closely associated in families with a member with asthma. This observation is in accordance with those of previous studies suggesting that atopy is associated with asthma.[12,33] Conversely, in control families, AHR did not appear to be as strongly associated with atopy. Our study results are also in keeping with the high prevalence of asymptomatic AHR reported in parents of children with asthma.[25,34]

Cockcroft, Murdock and Bercheid[6] reported that 4.5% of normal adults had asymptomatic AHR, whereas 12.7% of subjects with allergic rhinitis had asymptomatic AHR. In another study, Woolcock and associates[8] reported that 32% of adults with AHR had no asthma symptoms. Power and associates[7] showed an even higher prevalence of asymptomatic AHR in the general population. In our investigation, prevalence of asymptomatic AHR was 41.3% in the families with a member with asthma and 26.7% in the control families.

In addition, among the first-degree relatives of the subjects with asthma, we observed a higher prevalence of high IgE levels than among the relatives in control families. This prevalence appears to be associated with the proportion of subjects who have atopy (Table 4).[9,13,32]

A positive correlation between IgE levels and blood eosinophil counts as well as between IgE levels and atopic index has previously been found.[35,36] We found the same correlations and observed that these correlations held in all groups studied.

Finally, we observed a familial tendency to react to the same categories of allergens (Table 5). Contrary to the findings of Kuehr and associates,[37] this tendency does not appear to be more closely associated with the maternal history of atopy than with the paternal history of this condition.

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Conclusion

We found not only a higher prevalence of AHR, atopy and elevated serum IgE levels in the first-degree relatives of the subjects with asthma than in the control subjects from nonasthmatic families, but, most importantly, an increased expression of the atopic phenotype and a higher degree of AHR. Furthermore, we showed that asymptomatic AHR was more frequent in women than in men and in the families with a member with asthma than in the families with no subjects with asthma. Asymptomatic AHR was associated with higher atopic indices and serum IgE levels among these subjects. However, in subjects in the control group, asymptomatic AHR was less related to atopy than it was in the first-degree relatives of patients with asthma. This suggests that asymptomatic AHR, like asthma, is influenced by immune factors, possibly genetically determined, although its higher prevalence in women remains unexplained.

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Acknowledgements

We are grateful to Serge Simard for his help with statistical analysis and to Lori Schubert for reviewing the manuscript. Catherine Laprise was supported by the Fonds pour la formation de chercheurs et l'aide à la recherche.

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