Key words: bronchial responsiveness; gender; geography; prevalence; variability

Transcription

1 Geographic and Gender Variability in the Prevalence of Bronchial Responsiveness in Canada* Jure Manfreda, MD; Malcolm R. Sears, MD; Margaret R. Becklake, MD; Moira Chan-Yeung, MD; Helen Dimich-Ward, PhD; Hans C. Siersted, MD; Pierre Ernst, MD; Lamont Sweet, MD; Linda Van Til, DVM; Dennis M. Bowie, MD; and Nicholas R. Anthonisen, MD Objectives: Geographic variability in reported prevalences of asthma worldwide could in part relate to interpretation of symptoms and diagnostic biases. Bronchial responsiveness measurements provide objective evidence of a common physiologic characteristic of asthma. We measured bronchial responsiveness using the standardized protocol of the European Community Respiratory Health Survey (ECRHS) in six sites in Canada, and compared prevalences across Canada with international sites. Design: Samples of 3,000 to 4,000 adults aged 20 to 44 years were randomly selected in Vancouver, Winnipeg, Hamilton, Montreal, Halifax, and Prince Edward Island, and a mail questionnaire was completed by 18,616 individuals (86.5%). Preselected random subsamples (n 2,962) attended a research laboratory for examination including more detailed questionnaires, lung function testing including methacholine challenge, and skin testing with 14 allergens. Results: Prevalences of bronchial hyperresponsiveness, measured as cumulative dose of methacholine required to produce a 20% fall from the post-saline solution FEV 1 < 1 mg, ranged from 4.9% (95% confidence interval [CI], 1.6 to 8.5) in Halifax to 22.0% (95% CI, 18.1 to 26.0) in Hamilton (median, 10.7%). In all Canadian sites, bronchial hyperresponsiveness was more prevalent in women than in men. Neither the geographic nor gender differences were accounted for by differences in age, smoking, skin test reactivity, or baseline FEV 1. Geographic- and gender-related variability changed little when only bronchial hyperresponsiveness associated with asthma-like symptoms was considered. Conclusions: A wide variability in bronchial responsiveness can occur within one country, almost as wide as the range found across all international sites participating in the ECRHS study and not explained by differences in gender, smoking, skin test reactivity, and FEV 1. While gender variability in the prevalence of bronchial responsiveness is likely due to hormonal and immunologic factors, geographic variability is likely to result from environmental factors. (CHEST 2004; 125: ) Key words: bronchial responsiveness; gender; geography; prevalence; variability Abbreviations: CI confidence interval; ECRHS European Community Respiratory Health Survey; PD 20 cumulative dose of methacholine required to produce a 20% fall from the post-saline solution FEV 1 ; PEI Prince Edward Island *From the Department of Medicine (Drs. Manfreda and Anthonisen), University of Manitoba, Winnipeg, MB; Firestone Institute for Respiratory Health (Drs. Sears and Siersted), St. Joseph s Healthcare and McMaster University, Hamilton, ON; Respiratory Epidemiology Unit (Drs. Becklake and Ernst), Joint Departments of Epidemiology and Biostatistics and of Occupational Health, McGill University, Montreal, QC; Respiratory Division (Drs. Chan-Yeung and Dimich-Ward), Department of Medicine, University of British Columbia, Vancouver, BC; Department of Health and Social Services (Drs. Sweet and Van Til), Charlottetown, PE; and Department of Medicine (Dr. Bowie), Dalhousie University, Halifax, NS, Canada. Asthma remains a common and problematic condition, and appears to have increased in prevalence and perhaps severity. 1 International comparative studies in adults 2 and children 3 in many countries including Canada 4,5 have documented significant geographic variability in prevalence among different countries and among regions within coun- Support was provided by the National Health Research and Development Program, Health Canada, Glaxo Canada, and Province of Prince Edward Island. Manuscript received August 6, 2003; revision accepted November 18, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Jure Manfreda, MD, University of Manitoba, Department of Medicine, RS-115, 810 Sherbrook St, Winnipeg, MB, Canada R3A 1R8; manfred@ms.umanitoba.ca CHEST / 125 / 5/ MAY,

2 tries. We carried out a two-stage study of asthmarelated symptoms and conditions in six locations across Canada. We previously reported 4 the results of the first stage of the study: the prevalence of asthma symptoms varied significantly among the Canadian sites studied. For example, the prevalence of wheezing varied between 23.5% and 33.3%, chest tightness varied between 15.5% and 20.2%, nocturnal attacks of shortness breath varied between 7.5% and 10.2%, and nocturnal attacks of coughing varied between 29.9% and 35.3%. Depending on the site, 6.8 to 10.0% reported asthma attacks in the last year, and 4.8 to 7.8% reported current use of asthma medication. The prevalence of asthma symptoms in Canada was relatively high in comparison with other countries. 4 Reliance on symptoms and diagnoses as sole evidence of the prevalence of asthma may be misleading, as there are different responses to manifestations of respiratory illness that may or may not be labeled as due to asthma. 6 In epidemiologic studies, asthma can be defined by the concurrence of symptoms and airway hyperresponsiveness. 7 In the European Community Respiratory Health Survey (ECRHS), 8 assessment of bronchial responsiveness to methacholine using a standardized protocol was included to provide an objective physiologic measure to complement clinical and historical data suggesting asthma. In this article, we report the results of stage 2 of the study. The objective of the second stage was to determine geographic variability in the prevalence of bronchial responsiveness to methacholine, including its age and gender characteristics, among 20- to 44-year-old adults in six sites across Canada. By adopting the principal instruments and design characteristics of the ECRHS protocol, 8,9 we also compared the experience of Canadian and international sites in the ECRHS. Sample Selection Materials and Methods As previously reported, 4 a multicenter, two-stage, epidemiologic study was conducted between March 1993 and November 1994 in six locations across Canada. 4 For stage 1, samples of 3,000 to 4,000 adults aged 20 to 44 years were randomly selected in Vancouver, Winnipeg, Hamilton, Montreal, Halifax, and Prince Edward Island (PEI). Except in PEI, random-digit telephone dialing was used to identify eligible individuals. For each location, a random sample of 18,000 telephone numbers was generated. Interviewers systematically called the generated numbers and, following an appropriate introduction, determined if the number was residential and if there were eligible subjects in the household. If there was no answer, the interviewer called up to seven times, varying the day and time. If more than one household member was eligible, the resident to be included was identified using a predetermined sampling scheme. A short mail questionnaire about asthma symptoms was sent to selected individuals. This was repeated to nonresponders after 3 weeks. Those who did not respond to the second mailing were telephoned and encouraged to return the completed questionnaire by mail or to complete it over the telephone. In PEI, the procedure was essentially the same except that eligible individuals were identified from the population registry of the universal Provincial Health Plan. The total sample consisted of 21,449 individuals, of whom 18,616 individuals (86.5%) completed the mail questionnaire. In stage 2, preselected random subsamples of those participating in stage 1 were invited to attend a research laboratory for examination including more detailed questionnaires, lung function testing including methacholine challenge, determination of total IgE, and skin testing with 14 allergens. 10 To identify the subsample, a random sample of telephone numbers was selected. If these numbers led to identification of an eligible individual, this individual was invited to the research laboratory after the completed mail questionnaire has been received. At the time of contact and completing the questionnaire, neither the participant nor the study technicians knew about the selection for the stage 2 of the study. The objective was to examine 500 to 600 people in the laboratory at each site. To achieve this, approximately 36% of respondents to the mail questionnaire were selected for the laboratory examination. In all six locations, identifying subjects, completing the mail questionnaire, and laboratory examinations took approximately 12 months to complete. Spirometry In all sites, a dry rolling-seal spirometer (Grasbe-Andersen; Spirotech Division; Atlanta, GA) was used. Daily calibration with a 3-L syringe and testing procedures were those recommended by the American Thoracic Society. 11 The Lung Health Study protocol and computer software for spirometry were used. 12 Bronchial Responsiveness Methacholine solutions were prepared in concentrations of 0.39 mg/ml, 1.56 mg/ml, 6.25 mg/ml, and 12.5 mg/ml in normal saline solution, 10 using acetyl-b-methylcholine chloride powder. Mefar compressed-air dosimeters (MB3; Mefar; Bovezzo, Italy) calibrated to an output of ml per inhalation were used to administer saline solution or methacholine. 13 If FEV 1 decreased by 10% after normal saline solution, testing was discontinued; otherwise, the subject followed one of two protocols for methacholine challenge. 13 A long protocol (doubling doses) was followed by subjects with recent symptoms of asthma; all other subjects followed a short protocol (quadrupling doses). Both protocols provided the same cumulative dose of methacholine. The cumulative dose of methacholine required to produce a 20% fall from the post-saline solution FEV 1. (PD 20 ) was calculated by fitting an exponential curve to the decline in FEV 1 with log dose of methacholine. 13 For purposes of international comparison, we have used a PD 20 1 mg as indicating bronchial hyperresponsiveness. 13 The log slope was calculated by regressing the percentage decrease in FEV 1 on log 10 of the dose. The transformed log slope [100/log (slope 10)] was used in the analysis. 14 A low slope corresponds to increased bronchial responsiveness. Skin Testing Each subject was tested with 14 allergens (Hollister-Stier; Spokane, WA) using a prick lancetter: cat, cockroach, Dermato Clinical Investigations

3 phagoides pteronyssinus, Dermatophagoides farinae, olive, birch, east/west tree mixture, Timothy grass, Kentucky blue grass, common ragweed, Cladosporium herbarum, Penicillium, Alternaria alternata, and Aspergillus, together with a negative and a positive control. The weal diameter was measured after 15 min at its widest point and at 90 to the diameter at the midpoint. The two diameters were averaged. A subject was considered to be positive if the weal diameter of at least one allergen was 2 mm greater than the diameter of the negative control. Statistical Analysis We estimated for each site the overall and gender-specific prevalence (percentage) of PD 20 1 mg with 95% confidence interval (CI) and the mean slope with 95% CI. The direct method, as previously described, 2 was used for adjusting prevalences for gender and age. Nonparticipation was assessed by comparing participants and nonparticipants; the prevalence of PD 20 1 mg was adjusted for gender, age, smoking, and wheezing by the direct method to the distribution of these variables in all subjects who completed stage 1. 2 statistic and analysis of variance were used to test if discrete (PD 20 1 mg) and continuous (slope) variables, respectively, varied significantly across sites. Multiple logistic regression analysis was used to determine if site and gender differences were independent of age, FEV 1, and skin testing results. 15 Results were considered significant at p 0.05 or if 95% CIs did not overlap. The study was approved by ethics review boards from all participating institutions. Results In stage 1 of our study, 18,616 subjects 20 to 44 years old (86.5%) responded to the mail questionnaire. The number of subjects per center ranged from 2,959 to 3,408, with a slight female dominance in all centers (55.2% women overall). 4 Of these, 2,962 subjects (15.9%) attended the stage 2 laboratory examination. Table 1 shows participation rates by site: 499 to 599 per site attended except in Halifax, where only 255 participated. Stage 2 participants were similar to nonparticipants with respect to gender distribution (55.4% women vs 55.5% men, p 0.258); however, they were less likely to be smokers (26.1% vs 32.2%, p 0.001) and more likely to report asthma symptoms (30.8% vs 26.8%, p 0.001). Methacholine challenge was attempted by 2,307 subjects (77.9%), of whom 2,249 subjects (97.5%) provided sufficient data to estimate PD 20 (if achieved) and slope using the ECRHS computer modeling program. 9,13 Methacholine challenge was not carried out in 655 subjects. We excluded 110 individuals because of heart problems, epilepsy, use of beta-blockers, pregnancy, or breastfeeding. In addition, 113 subjects refused all lung function testing, and a further 371 subjects refused the methacholine challenge. Among those with baseline lung function results, 26 individuals were excluded because FEV 1 was 70% of the predicted value or 1.5 L, as were 35 subjects with 10% fall in FEV 1 after saline solution. Table 2 shows the percentage (95% CI) of individuals with PD 20 1 mg and the mean of the (transformed log) slope with 95% CI for the Canadian sites. Both values are adjusted for age and gender but not for nonparticipation, to be comparable with other ECRHS reports. 13 Adjustment for nonparticipation changed prevalence estimates by 2% in any site. There were significant differences between Canadian sites with respect to both the prevalence of subjects with PD 20 1 mg and the average slope. The highest prevalence of PD 20 1 mg (and the lowest average slope) were found in Hamilton followed by Vancouver. The lowest prevalence of PD 20 1 mg and the highest average slope were found in Halifax. In Figure 1, the prevalence of bronchial responsiveness to methacholine measured as PD 20 1mg in Canadian sites is compared to that reported from 35 sites in 16 countries sorted by median value for prevalence. 13 The variation in prevalence across the six Canadian sites covers almost the whole range of the international variation. Canada, with a median prevalence of 10.7%, is placed approximately one third between the lowest (Iceland, 7.2%) and the highest (New Zealand, 27.6%) prevalences. The position of the Canadian median (10.7%) is not affected by either high prevalence in Hamilton (22.0%) or low prevalence in Halifax (4.9%). Two Table 1 Methacholine Challenge in Selected Subjects Site Stage 1 Participants, No. Stage 2 Participants, No. (%) Methacholine Challenged, No. (%)* Vancouver 2, (17.2) 391 (76.7) Winnipeg 2, (20.1) 519 (86.6) Hamilton 3, (14.8) 431 (85.7) Montreal 2, (16.9) 367 (73.5) Halifax 2, (8.6) 183 (71.8) PEI 3, (17.9) 416 (69.8) Total 18,616 2,962 (15.9) 2,307 (77.9) *Percentage of stage 2 participants. Table 2 Bronchial Responsiveness by Site PD 20 1mg* Slope Vancouver 16.9 ( ) 7.21 ( ) Winnipeg 9.2 ( ) 7.90 ( ) Hamilton 22.0 ( ) 6.86 ( ) Montreal 11.9 ( ) 7.67 ( ) Halifax 4.9 ( ) 8.12 ( ) PEI 9.4 ( ) 7.83 ( ) *Data are presented as % (95% CI). Data are presented as mean slope (95% CI). A low slope corresponds to increased responsiveness in the population. CHEST / 125 / 5/ MAY,

4 Figure 1. Prevalence of PD 20 1 mg in Canada and internationally (international data are from Chinn et al 13 ). Canadian sites: Halifax, ΠWinnipeg, F PEI, Montreal, Vancouver, f Hamilton. Canadian sites, Hamilton (22.0%; 95% CI, 18.1 to 26.0) and Vancouver (16.9%; 95% CI, 13.2 to 20.8) are significantly above the median for the 35 international sites (13.0%). 13 The distribution of locations and countries by slope was with few exceptions the same as for PD 20 1 mg (data not shown). In all Canadian sites, the prevalence of PD 20 1 mg (Fig 2) was higher, and the mean slope (not shown) was lower, for women than for men. Variation between sites was significant for both genders due to the high prevalence of PD 20 1 mg in both genders in Hamilton and Vancouver. The prevalence of bronchial hyperresponsiveness was higher in women at all sites, most strikingly in Hamilton where 28.7% (95% CI, 22.8 to 34.6) of women showed a PD 20 1 mg in comparison with 15.3% (95% CI, 10.3 to 20.2) of men. In contrast, in Halifax, bronchial hyperresponsiveness was uncommon, being found in only 5.4% of women and 3.7% of men. The prevalence of PD 20 1 mg and the mean slope did not change significantly with age between 20 years and 44 years in men or women. Figure 2. Prevalence of PD 20 1 mg in six Canadian sites by gender ( men, women). Table 3 shows that the likelihood of bronchial hyperresponsiveness (PD 20 1 mg) was increased in women in comparison with men, in those with lower FEV 1, in smokers in comparison with nonsmokers (combined past smokers and neversmokers), and in those with at least one positive skin test result. It was independent of age. However, differences between sites were not due to differences in distributions of FEV 1 percentage of predicted, gender, smoking, and skin test reactivity between sites. Essentially the same results were obtained for the slope as an indicator of bronchial responsiveness (data not shown). Because Canadian sites ranked high in international comparison with respect to prevalence of asthma symptoms, 4 and relatively low in the present comparison of bronchial responsiveness, we plotted the 35 international 13 and the 6 Canadian sites by the level of PD 20 1 mg and the percentage prevalence of diagnosed asthma reported in the stage 1 mail questionnaire (Fig 3). 2,4 Individuals with diagnosed asthma were those who responded positively to questions, Have you had an attack of asthma in the last 12 months? or Are you currently using any medication (including inhalers, aerosols, or tablets) for asthma? While there is a general relationship between the level of PD 20 1 mg and the prevalence of diagnosed asthma overall, there is no relationship for the Canadian sites. The correlation coefficient (r) for the relationship in Figure 3 is 0.45 (p 0.003); by excluding Halifax, r equaled 0.54 (0.0003); and by excluding all Canadian centers, r was 0.61 (p ). The prevalence of diagnosed asthma tends to be higher at higher prevalence of Table 3 Odds Ratios for Bronchial Hyperresponsiveness (PD 20 < 1 mg)* Variables Odds Ratio (95% CI) Univariate Multivariate* Gender (women vs men) 1.76 ( ) 2.16 ( ) Age (1 year of age) 0.99 ( ) 1.00 ( ) Smoking (smokers vs 1.48 ( ) 1.48 ( ) nonsmokers) Skin test 2.39 ( ) 2.45 ( ) FEV 1 % predicted (1 U) 0.95 ( ) 0.95 ( ) Site PEI Halifax 0.49 ( ) 0.42 ( ) Montreal 1.24 ( ) 1.30 ( ) Hamilton 2.83 ( ) 2.60 ( ) Winnipeg 1.08 ( ) 0.89 ( ) Vancouver 2.1 ( ) 2.12 ( ) *Based on multiple logistic regression analysis with PD 20 1mgas the dependent variable. Odds ratios are adjusted for all variables in the model. At least one positive ( 2 mm) test result vs none Clinical Investigations

5 Figure 3. The relationship between the prevalence of diagnosed asthma and PD 20 1 mg for Canadian and international sites. Canadian sites: Halifax, ΠWinnipeg, F PEI, Montreal, Vancouver, f Hamilton. Diagnosed asthma is from Manfreda et al 4 (Canadian sites) and ECRHS 2 (international sites). PD 20 1 mg is from Chinn et al 13 for international sites. Individuals with diagnosed asthma are those who reported an asthma attack in the last 12 months or current use of asthma medication. PD 20 1 mg, although at each level there is substantial variability. At each level of PD 20 1mg, Canadian sites are grouped with those with a high prevalence of diagnosed asthma. Among those with low prevalences of PD 20 1 mg, Halifax is an outlier because of the high prevalence of diagnosed asthma. However, among sites with a prevalence of PD 20 1 mg between 20% and 25%, there are four sites with relatively low prevalence of diagnosed asthma: Albecete (Spain), Montpellier and Bordeaux (France), and Aarhus (Denmark) [Fig 3, lower right]. The distribution of symptomatic bronchial hyperresponsiveness was compared across the sites by gender. Symptomatic individuals were those who reported that, in the last 12 months, they had wheezing or tightness in the chest, had been woken up by an attack of shortness of breath or coughing, had an asthma attack, or were currently receiving asthma medication. 4 Of the 300 subjects (13.3%) who had PD 20 1 mg, 227 subjects (75.7% of those with hyperresponsiveness, 10.1% of those providing valid challenge data) reported symptoms 2,4 in the last year; 183 subjects (61.0% and 8.1%, respectively) reported the symptom of wheezing. The distribution of symptomatic bronchial hyperresponsiveness by site and gender (Fig 4) was similar to that of all (combined symptomatic and nonsymptomatic) subjects with bronchial hyperresponsiveness (Fig 2). Discussion In the absence of a precise definition of asthma, methacholine challenge has become one of the Figure 4. Prevalence of PD 20 1 mg with symptoms by gender ( men, women) in six Canadian sites. Individuals with symptoms are those who reported to have had in the last 12 months wheezing or tightness in the chest, were woken up by an attack of shortness of breath or coughing, had an asthma attack, or were currently receiving asthma medication. standard methods for objective assessment of bronchial responsiveness, which correlates broadly with the presence and severity of asthma, and has been widely used in epidemiologic studies Most consensus definitions of asthma include variable airflow obstruction and airway hyperresponsiveness. 19 Toelle et al 7 suggested that a useful definition of current asthma for epidemiologic purposes was the presence of recent symptoms together with objective evidence of airway hyperresponsiveness. The response rate to the stage 2 invitation in the Canadian sites was 38.4%, with a range of 24.6 to 57.5%. This is within the range (12.2 to 90.3%) but below the average (49.2%) for international sites in ECRHS. 13 However, in Canada a larger proportion of those who came to the laboratory was successfully challenged with methacholine (77.9%; range, 69.7 to 86.5%; in comparison with 73.2% internationally; range, 45.3 to 90.8%). The overall low participation rate contrasts with an excellent response to the mail questionnaire, 4 and may relate to the requirement for 2 h of laboratory testing time that many 20- to 44-year-old subjects were reluctant to contribute. Adjustment for nonparticipation did not change estimates of the prevalence of airway responsiveness. The selection of the population for the methacholine challenge may have introduced some bias. Firstly, the stage 2 subsample had a slightly greater prevalence of symptoms than the stage 1 sample, which may increase the apparent prevalence of bronchial responsiveness in the general population. However, the lung function of those performing methacholine challenge was greater than the overall mean lung function in the subsample and the function of those not performing the methacholine challenge, in part due to exclusion criteria for safety of testing. This would have the opposite effect, decreasing the apparent prevalence of bronchial responsiveness. Responsiveness was increased in UK partici- CHEST / 125 / 5/ MAY,

6 pants in ECRHS with decreased function. 20 The extent of these biases in our study cannot be easily assessed, but as they act in different directions the net effect would be to minimize bias. The data presented may therefore somewhat overestimate or underestimate the true prevalence of bronchial responsiveness in the population. As the same exclusion criteria were used in each Canadian site and internationally, comparisons between sites and countries should remain valid. However, the variability in overrepresentation of symptomatic subjects among Canadian centers adds complexity to determining how well the reported prevalence rates reflect the original population sample. Results of methacholine challenge are significantly affected by methods of testing and nebulizers used to deliver stimuli. These problems were minimized by adopting the ECRHS protocol, where measurement of responsiveness to methacholine was standardized to provide a comparison of an objective marker of asthma among populations where labeling and diagnosis of asthma might vary for language or cultural reasons. As all ECRHS sites followed the same protocol and used the same dosimeter, these differences between international and national sites were minimized although they were probably not completely excluded. Major differences due to technical factors were also unlikely as all Canadian research technicians were trained in one place. However, there are several methodologic issues that must be addressed in interpreting bronchial responsiveness data, including participation rate, selection bias, baseline lung function, and seasonal influences on bronchial responsiveness. Chinn et al 9 described methods of challenge and expression of results as PD 20 and dose-response slope estimates, finding slightly greater repeatability for least-square slope. However, Chinn et al 21 reported significant variation in Mefar dosimeter output. Variability in results was lessened by use of the log slope to express bronchial responsiveness. 14,21 Adjustment for nebulizer output calibration affected calculation of PD 20 but had much less effect on calculation of dose-response slope. 13 We have found substantial regional variation in bronchial responsiveness across Canada for men and women combined (Table 2) as well as separately (Fig 2). This variability is greater than that in symptoms previously reported. 4 Of particular interest was the much higher prevalence of PD 20 1 mg, particularly in women, in Hamilton, and the low prevalence in Halifax (Table 2, Fig 2). While the high prevalence of bronchial hyperresponsiveness is consistent with high prevalence of asthma symptoms in Hamilton, this is not the case in Halifax. 4 Differences between Canadian sites cannot be explained by climatologic and air pollution characteristics, although pollution levels are somewhat higher in Hamilton than in other Canadian sites, particularly PEI. 4 They can also not be explained by differences between sites in gender distribution, FEV 1 percentage of predicted, smoking, or atopy defined as positive skin reactivity (Table 3). The low prevalence of bronchial hyperresponsiveness in Halifax was not due to technical problems or selection of more healthy subjects, although the participation rate in Halifax was lower than in other Canadian sites (Table 1). Halifax is not an isolated outlier; in most countries with several sites studied, outliers in either direction can be identified, for example, Albecete in Spain. 13 Our study confirmed previously reported gender difference in the 20- to 44-year-old population in bronchial responsiveness Similarly to other studies, 25,26 we found that bronchial hyperresponsiveness (PD 20 1 mg) was related to lower FEV 1 percentage of predicted. However, as in the study by Leynaert et al, 24 the difference between men and women was not explained by smaller airway calibers of women, or a greater prevalence of symptoms in women, as even stronger gender differences were found in asymptomatic subjects. 22 In Sweden, bronchial hyperresponsiveness was recorded in 15.0% of women compared with 10.6% of men. 23 Our finding of the higher prevalence for increased bronchial hyperresponsiveness in women compared to men during their reproductive years (ie, the 20- to 44- year-age group) coincides with the finding of a higher incidence of asthma in women vs men in their reproductive years The impact of sex hormones on bronchial responsiveness has not been well studied, but evidence from studies of premenstrual asthma, and of the effect of hormone replacement therapy on asthma, has led to the view that increased estrogen levels may be associated with increased airway inflammation Gender differences have also led to the suggestion that the higher prevalence of bronchial hyperresponsiveness in women might relate to a greater susceptibility to cigarette smoke and indoor air pollutants including gas cooking and environmental tobacco smoke. 22 In Canada, we found the greatest gender difference in Hamilton, a city characterized by heavy industry, mainly steel manufacturing, with somewhat higher mean levels of air pollution than other Canadian cities studied. 4 This raises the possibility that bronchial responsiveness may reflect susceptibility to outdoor as well as indoor air quality. Compared with international sites, the Canadian median prevalence of bronchial responsiveness was just above one third of the medians of widely disparate countries. 13 Only two Canadian prevalence rates (Hamilton and Vancouver) were above the 1662 Clinical Investigations

7 ECRHS median. 13 This contrasts with reported symptoms, where Canada had one of the highest prevalence rates. Hence, symptoms were not as often corroborated by measurements of airway responsiveness. The discrepancy between prevalence of asthma symptoms and prevalence of bronchial responsiveness with respect to international comparisons might be partially explained by use of antiinflammatory medications, which may lower the prevalence of bronchial responsiveness in the population. The prevalence of using inhaled antiinflammatory medications in the last 12 months before the survey was 3.3% in Vancouver, 3.5% in Winnipeg, 6.3% in Hamilton, 5.2% in Montreal, 6.6% in Halifax, and 3.8% in PEI. The use of these medications in Canada was lower than in Australia and New Zealand, similar to the United Kingdom, and higher than in other participating countries. 33 Canadian data show substantial within-country variability, as seen in other ECHRS countries with several sites, for example Spain, United Kingdom, and France. Data from countries with only one center may be misleading with respect to the real variability in the country. The United States, for example, is represented in ECRHS with only one site (Portland, OR). The prevalence of both diagnosed asthma (7.1%) in stage 1 and PD 20 1mg (18.3%) in Portland 2,13 was very similar to the prevalence of diagnosed asthma (6.8%) 4 and PD 20 1 mg (16.9%) in Vancouver, a city with a similar environment. Figure 3 shows that lack of a close relationship between the prevalence of PD 20 1 mg and prevalence of symptoms is characteristic not only of Canadian data but also of many countries participating in ECRHS. This may indicate a fundamental limitation of a single bronchial responsiveness measurement. This measurement reflects the state of the airways at the time of testing, which may vary depending on the seasonal allergen exposure, intercurrent infection, or drug therapy. 34 Although our study was conducted over a 12-month period to minimize this concern, in any individual there may well be a discrepancy between reported symptoms over 12 months and methacholine responsiveness measured once only at the end of that period. While there is no precise relationship between clinical asthma and bronchial hyperresponsiveness, the latter remains a useful tool in epidemiology providing a measure of the presence of airway disease somewhat more specific for asthma than are symptoms alone. We have previously reported a comparison of results of methacholine challenge using this Mefar dosimeter method 35 with results obtained from the 2-min tidal breathing method of Cockroft et al. 36 This showed consistency of positive and negative results between the two methods (agreement 89.4%, statistic 0.78), and a highly significant correlation between methods. A PC 20 8 mg/ml by the tidal breathing method correlated best with a PD 20 by the Mefar method of 0.5 mg. 35 Each halving or doubling of PC 20 cut-point for categorizing airway hyperresponsiveness was associated with a halving or doubling of the PD 20 providing the highest statistic and the highest percentage agreement, suggesting a linear relationship between doubling doses of PD 20 and doubling concentrations of PC 20. Hence, studies of PD 20 to a dose of 1.0 mg cover the range of responsiveness examined by the tidal breathing technique up to concentrations of 16 mg/ml. In summary, the prevalence of bronchial hyperresponsiveness to methacholine across Canada varied by region, and by gender, with highest rates among women especially in Hamilton. The prevalence of bronchial hyperresponsiveness in Canada was intermediate among world values. Geographic variability could not be explained by differences between sites in gender distribution, low lung function, smoking, or atopy defined as positive skin reactivity. Some other, so far unknown, environmental factors are likely responsible. ACKNOWLEDGMENT: We thank Professor S. Chinn for assistance with the statistical analysis. References 1 Hansen EF, Rappeport Y, Vestbo J, et al. Increase in prevalence and severity of asthma in young adults in Copenhagen. Thorax 2000; 55: European Community Respiratory Health Survey. Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1996; 9: The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998; 12: Manfreda J, Becklake MR, Sears MR, et al. Prevalence of asthma symptoms among adults aged years in Canada. Can Med Assoc J 2001; 164: Habbick BF, Pizzichini MMM, Taylor B, et al. Prevalence of asthma, rhinitis and eczema among children in 2 Canadian cities: the International Study of Asthma and Allergies in Childhood. Can Med Assoc J 1999; 160: Lundback B, Ronmark E, Jonsson E, et al. Incidence of physician-diagnosed asthma in adults: a real incidence or a result of increased awareness? Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med 2001; 95: Toelle BG, Peat JK, Salome CM, et al. Towards a definition of asthma for epidemiology. Am Rev Respir Dis 1992; 146: Burney PGJ, Luczynska C, Chinn S, et al. The European Community Respiratory Health Survey. Eur Respir J 1994; 7: CHEST / 125 / 5/ MAY,

8 9 Chinn S, Burney PGJ, Britton JR, et al. Comparison of PD 20 with two alternative measures of response to histamine challenge in epidemiological studies. Eur Respir J 1993; 6: European Commission, Directorate General XII. Protocol for the European Community Respiratory Health Survey. Luxembourg: Office for Official Publications, American Thoracic Society. Standardization of spirometry, 1987 update. Am Rev Respir Dis 1987; 136: Enright PL, Johnson LR, Connett JE, et al. Spirometry in the lung Health Study: 1. Methods and quality control. Am Rev Respir Dis 1991; 143: Chinn S, Burney P, Jarvis D, et al, on behalf of the European Community Respiratory Health Survey (ECRHS). Variation in bronchial responsiveness in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1997; 10: Chinn S. Methodology of bronchial responsiveness. Thorax 1998; 53: Armitage P, Berry G, Matthews JNS. Statistical methods in medical research. 4th ed. Oxford, UK: Blackwell Science, Burrows B, Sears MR, Flannery EM, et al. Relations of bronchial responsiveness to allergy skin test reactivity, lung function, respiratory symptoms, and diagnoses in thirteen year old New Zealand children. J Allergy Clin Immunol 1995; 95: Basagana X, Sunyer J, Zock J-P, et al. Incidence of asthma and its determinants among adults in Spain. Am J Respir Crit Care Med 2001; 164: Richter K, Heinrich J, Jorres RA, et al, for the INGA Study Group. Trends in bronchial hyperresponsiveness, respiratory symptoms and lung function among adults: West and East Germany. Respir Med 2000; 94: Sears MR. The definition and diagnosis of asthma. Allergy 1993; 48: Chinn S, Jarvis D, Luczynska C, et al. Individual allergens as risk factors for bronchial responsiveness in young adults. Thorax 1998; 53: Chinn S, Arossa WA, Jarvis DL, et al. Variation in nebulizer aerosol output and weight output from the Mefar dosimeter: implications for multicentre studies. Eur Respir J 1997; 10: Leynaert B, Liard R, Bousquet J, et al. Lessons from the French part of the European Community Respiratory Health Survey (ECRHS). Allergy Clin Immunol Int 1999; 11: Norrman E, Plaschke P, Bjornsson E, et al. Prevalence of bronchial hyper-responsiveness in the southern, central and northern parts of Sweden. Respir Med 1998; 92: Leynaert B, Bousquet J, Henry C, et al. Is bronchial hyperresponsiveness more frequent in women than in men? A population based study. Am J Respir Crit Care Med 1997; 156: De Meer G, Heederik D, Postma DS. Bronchial responsiveness to adenosine 5 -monophosphate (AMP) and methacholine differ in their relationship with airway allergy and baseline FEV 1. Am J Respir Crit Care Med 2001; 165: Ichinose M, Takahashi T, Sugiura H, et al. Baseline airway responsiveness and its reversible component: role of airway inflammation and airway calibre. Eur Respir J 2000; 15: Becklake MR, Kauffmann F. Gender differences in airway behaviour over the human life span. Thorax 1999; 54: Kauffmann F, Becklake MR. Maladies obstructives pulmonaires: un paradigme de la complexite des differences de sante entre hommes et femmes. In: Saurel-Cubizolles MJ, Blondell B, eds. La sante des femmes. Paris, France: Flammarion, Medecine et Sciences, 1996; De Marco R, Locatelli F, Sunyer J, et al, and the European Community Respiratory Health Survey Study Group. Differences in incidence of reported asthma related to age in men and women: a retrospective analysis of the data of the European Respiratory Health Survey. Am J Respir Crit Care Med 2000; 162: Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. Am J Respir Crit Care Med 1995; 152: Mueller JE, Frye C, Brasche S, et al. Association of hormone replacement therapy with bronchial hyper-responsiveness. Respir Med 2003; 97: Haggerty CL, Ness RB, Kelsey S, et al. The impact of estrogen and progesterone on asthma. Ann Allergy Asthma Immunol 2003; 90: Janson C, Chinn S, Jarvis D, et al, on behalf of the European Community Respiratory Health Survey. Physician-diagnosed asthma and drug utilization in the European Respiratory Health Survey. Eur Respir J 1997; 10: Ulrik CS, Backer V. Longitudinal determinants of bronchial responsiveness to inhaled histamine. Chest 1998; 113: Siersted HC, Walker CM, O Shaughnessy AD, et al. Comparison of two standardized methods of methacholine inhalation challenge in young adults. Eur Respir J 2000; 15: Cockroft DW, Killian DN, Melon JA, et al. Bronchial reactivity to inhaled histamine: a method and a clinical survey. Clin Allergy 1977; 7: Clinical Investigations