Outcome in adulthood of asymptomatic airway hyperresponsiveness to histamine and exerciseinduced bronchospasm in childhood Celeste Porsbjerg, MD*; Marie-Louise von Linstow, MD*; Charlotte Suppli Ulrik, MD, DMSc†; Steen Christian Nepper-Christensen, MD*; and Vibeke Backer, MD, DMSc*
Background: Studies of the clinical outcome in adulthood of asymptomatic airway hyperresponsiveness (AHR) to histamine or exercise-induced bronchospasm (EIB) detected in childhood in general population samples are sparse and have produced conflicting results. Objective: To describe the outcome of asymptomatic AHR to histamine and EIB. Methods: Data from a 12-year follow-up study of a random population sample of individuals aged 7 to 17 years at enrollment were analyzed; only individuals without asthma at enrollment were included in the analysis. AHR to inhaled histamine, EIB, lung function, and sensitization to aeroallergens were measured. Results: Among the 281 nonasthmatic participants studied, 58 (22%) had AHR to histamine, 33 (12%) had EIB, and 82 (29%) had AHR to histamine and/or EIB. At follow-up, 37.9% of individuals with AHR to histamine and 30% of individuals with EIB had developed current asthma, compared with only 5% of individuals in whom these test results were negative. In patients with AHR to histamine, parental asthma (odds ratio [OR], 12.6; 95% confidence interval [CI], 1.5–108.5), furred pets ownership (OR, 6.0; 95% CI, 1.2–19.6), and dermatitis and/or rhinitis in childhood (OR, 2.2; 95% CI, 1.1–5.1) predicted the subsequent development of asthma, whereas no risk factors for the development of asthma could be identified in individuals with EIB. Conclusion: Asymptomatic AHR to histamine and EIB in childhood predict the subsequent development of asthma in adulthood. A genetic disposition to asthma, furred pets ownership, and concomitant rhinitis or dermatitis increase the risk of asthma development in individuals with AHR to histamine. Ann Allergy Asthma Immunol. 2005;95:137–142.
INTRODUCTION Airway hyperresponsiveness (AHR) to histamine or methacholine is induced by a direct effect of the agents on the smooth muscle cells of the airways, whereas AHR to an indirect stimulus such as exercise, ie, exercise-induced bronchospasm (EIB), is induced by mediators released from inflammatory cells situated in the mucosal layer in response to the stimulus.1 This presumably explains why, in diagnosing asthma, a positive exercise test result is more specific but less sensitive than AHR to histamine or methacholine, assuming that a certain degree of airway inflammation and level of exercise is required for the exercise test result to be positive.1 Airway inflammation and AHR are characteristics of asthma, but both conditions are seen separately in asymptomatic individuals, suggesting that asthma symptoms arise when both are present.2 AHR to histamine or methacholine in
* Respiratory Research Unit, Department of Internal Medicine, Bispebjerg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark. † Department of Respiratory Medicine, Hvidovre Hospital, University Hospital of Copenhagen, Copenhagen, Denmark. Received for publication August 31, 2004. Accepted for publication in revised form November 29, 2004.
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asymptomatic children predicts the subsequent development of asthma symptoms in a significant number of cases. EIB in asymptomatic children has not been described extensively, but prospective data suggest that although EIB is a risk factor for subsequent development of asthma symptoms, the predictive value of a positive test result is surprisingly low, considering that a positive exercise test result is more specific than a direct test in diagnosing active asthma.3 Patients with EIB presumably have active airway inflammation and as such would be expected to be at a higher risk of developing symptoms of airway obstruction than patients with AHR to histamine, who do not necessarily have airway inflammation. Not all patients with AHR develop asthma, but the presence and degree of inflammation seem to increase the risk of asthma development in this subgroup of patients. Atopic manifestations, such as allergic sensitization, rhinitis, or dermatitis, in patients with AHR are potential indicators of airway and systemic inflammation, and the concomitant presence of these manifestations in patients with asymptomatic AHR may, therefore, increase the risk of subsequent asthma further.4 We used data obtained in a prospective epidemiologic study of a random population sample to investigate the outcome in adulthood of asymptomatic AHR to histamine or EIB observed in childhood, with regard to the risk of devel-
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opment of asthma and other atopic manifestations at the age of 19 to 29 years. METHODS A random sample of children and adolescents (mean age, 12 years; age range, 7–17 years) living in Copenhagen, Denmark, was drawn from the civil registration list in 1986 and invited to participate in the present study. All individuals were invited by letter to complete surveys in 1986 and 1998. Exclusion Criteria To avoid false-negative results on the skin prick test and bronchial provocation test, participants taking medication for asthma and allergy were asked not to use theophylline or an antihistamine for at least 24 hours or astemizole for 6 weeks. The use of short-acting inhaled bronchodilators was discontinued for 12 hours and long-acting inhaled bronchodilators for 24 hours. Participants were allowed to continue use of any inhaled or oral corticosteroid they had been taking to avoid any risk of asthma deterioration during a prolonged washout period. Case History All participants completed a written questionnaire concerning respiratory and allergic symptoms as related to themselves and their parents, current and former smoking habits, drinking habits, education, present job, family size, and physical activities. The questionnaire concerned respiratory symptoms and the definition of asthma and was adopted from studies by the American Thoracic Society, Division of Lung Disease, of the National Heart, Lung, and Blood Institute5,6 and Hopp et al.7,8 Asthma was defined by questionnaire criteria on the basis of the responses to the following questions: (1) Have you ever had asthma? (2) Does your breathing ever sound wheezy or whistling? (3) Do you have attacks of shortness of breath with wheezing? (4) Do you experience wheezing, chest tightness, cough, and breathlessness with any of the following: at rest, with exertion, with emotional stress, with exposure to cold air, with chest infections or head cold? (5) Do you experience wheezing after exposure to dust, fumes, mold, pollen, food, pets, or drugs? (6) Have you ever had attacks of wheezing, shortness of breath, or dry cough at night? (7) Have you ever been hospitalized or observed and treated by a physician for asthma? (8) Have you ever received medication for your asthma? (9) What was the medication used? (10) Did it help? (11) How old were you at your first asthma attack? (12) How many episodes of wheezing have you had during the least year? (13) How old were you at your last asthma attack? Asthma was defined on the basis of positive responses to questions 2, 3, and 4 and/or 5. Current asthma was defined as symptoms within the preceding 12 months. The questions concerning allergy and allergy-related factors were as follows: (1) Have you ever experienced allergy in your nose or eyes? (2) Have you ever had atopic dermatitis? (3) Do your parents or siblings have allergies?
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Skin Prick Testing All participants had a skin prick test performed with a standard panel of 10 common aeroallergens in Denmark: birch, grass, mugwort, horse, dog, cat, house dust mite (Dermatophagoides farinae and Dermatophagoides pteronyssinus), Cladosporium herbarium, and Alternaria iridis (ALKAbello, Hørsholm, Denmark). A wheal diameter ([d1 ⫹ d2]/ 2) of at least 3 mm was recorded as positive. Identical allergens and procedures were used at each of the 2 surveys, and atopy was defined as a positive skin prick test result to at least 1 of the 10 allergens. Pulmonary Function Testing The forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using a 7-L dry wedge spirometer (Vitalograph, Buckingham, England), which was calibrated weekly. Each measurement consisted of at least 3 maximal expiratory maneuvers from total lung capacity to residual volume with a variation of less than 5%. The highest FEV1 and FVC were used in the analysis. Histamine Challenge Testing AHR to inhaled histamine was measured using the method described by Cockcroft et al9 at both examinations. Aerosols of the test solution were generated by a Wright nebulizer (Aerosol Products Ltd, London, England). The first aerosol was saline solution (0.9%), followed by increasing concentrations of histamine (0.075 to 8.0 mg/mL in the first survey and up to 16.0 mg/mL in the second survey). The test was terminated when a decline of 20% or more in FEV1 from the postsaline value occurred or after the highest dose, and concentration of provoking stimulus that caused a 20% decrease in FEV1 (PC20) was calculated by linear interpolation from the individual log-dose response curve.10 A positive test result was defined as a PC20 less than 8 mg/mL in the first survey of smaller children and less than 16.0 mg/mL of histamine (AHR) in the second survey. Pregnant and lactating women were excluded from taking the histamine challenge test. Exercise Testing The exercise challenge test was only performed at enrollment (baseline study) in 1986. Bronchial hyperresponsiveness to exercise was tested by steady running on a 10% slopping treadmill for 6 minutes in a climate chamber (temperature, 21°C; relative humidity, 40%–50%).11 The speed was adjusted to maintain the heart rate between 160 and 180/min. The response was measured by the FEV1 before (baseline value) and 0, 1, 3, 5, 10, and 15 minutes after the test. At each time, the highest of the 3 measurements was recorded and bronchial hyperresponsiveness to exercise was calculated as the maximum decline in FEV1 from the prechallenge value, expressed as a percentage of reduction in lung function. A 10% decrease in FEV1 from baseline (EIB10) was regarded as positive. Furthermore, a 15% decrease in FEV1 from baseline (EIB15) was calculated. Participants with a prechallenge FEV1 less than 1.0 L were excluded from taking the exercise challenge test.
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Statistical Analysis The McNemar 2 test was used to asses significant differences between the prevalence of risk factors and outcomes between participants with and without AHR to histamine or EIB10 or EIB15. P values for each group are the result of a comparison between the following: (1) participants without AHR to histamine or EIB10 or EIB15 compared with participants with any of the 3; (2) participants with AHR to histamine compared with participants without AHR to histamine or EIB10 or EIB15; (3) participants with EIB10 compared with participants without AHR to histamine or EIB10 or EIB15; and (4) participants with EIB15 compared with participants without AHR to histamine or EIB10 or EIB15. Univariate logistic regression analysis was used to evaluate risk factors for current asthma at follow-up in participants with AHR to histamine and/or EIB10 or EIB15. Risk factors found to be significant in the univariate analysis (P ⬍ .05) were subsequently compared 2 by 2 in 2 tests, where no statistically significant interactions were found. Finally, the relative impact of these risk factors was evaluated in a multivariate logistic regression analysis. To test for any significant effect modifications between the effect of any included variable and that of any other included variable on the outcome, we performed formal statistical tests for primary interaction by generating interaction terms (parental asthma vs pets in childhood, parental asthma vs dermatitis or rhinitis, and pets in childhood vs dermatitis or rhinitis) and using them as covariates in addition to the main effects (sex and eversmoking) on the independent variable (current asthma at follow-up). Statistical analysis was performed using SPSS statistical software, version 10.1 (SPSS Inc, Chicago, IL). RESULTS Of the 983 children and adolescents invited to participate in the present study, 527 (54%) participated in the first survey
and 633 (64%) in the third survey. A total of 294 individuals (31%) participated in both surveys. Only data for the 281 individuals without any signs or symptoms of asthma in the first survey were used in the present analysis. No significant differences was found among the groups (ie, “stayers,” “dropouts,” and “newcomers” in the 2 surveys) with regard to anthropometric data, pulmonary function, AHR, and allergic diseases, indicating that the participants in the present analysis are representative of the entire sample. At the first survey, no statistically significant differences with regard to sex or age, lung function, positive skin prick test result, rhinitis, and dermatitis were observed between participants with and without AHR to histamine or EIB (Table 1). Of the 281 participants, 58 (22%) had AHR to histamine at the first survey, whereas 33 (12%) and 10 (4%) experienced EIB10 and EIB15 (Table 1). A total of 82 (29%) had AHR to histamine and/or EIB. The presence of a parental history of asthma and allergy, pet ownership in childhood, passive smoking in childhood, and wheezing in childhood was similarly distributed among groups (Table 1). When comparing participants with and without AHR to histamine, EIB10, or EIB15, no significant differences were apparent with regard to the presence of a positive skin prick test result, rhinitis, or dermatitis (Table 1). Furthermore, lung function (FEV1 and FEV1/FVC ratio) was similar in the different groups (Table 1). At follow-up, current asthma was significantly more common in participants with than without AHR to histamine or EIB15 at the first survey (22% and 30%, respectively, vs 5%) (Table 2). A total of 37.9% of participants with AHR to histamine reported having had asthma some time during the follow-up period, which was only the case for 11% of participants without AHR. In comparison, 30% of participants
Table 1. Clinical Characteristics According to Presence of AHR to Histamine or EIB in 281 Individuals Without Ashma at the Age of 7 to 17 Years*
Females Passive smoking in childhood Parental history of asthma Wheezing in childhood Furred pets in childhood Atopy Rhinitis (ever) Dermatitis (ever) FEV1 at age 7-12 y, mean (SD), % predicted FEV1/FVC at age 7-12 y, mean (SD), % EIB10 EIB15 AHR to histamine
No AHR or EIB (n ⴝ 202)
AHR (n ⴝ 58)
59.4 64.9 11.9 8.0 29.7 22.8 11.9 4.0 91.9 (10.1) 90.5 (6.4)† 0 0 0
50.0 63.8 12.1 10.3 34.5 25.9 13.8 8.6 90.0 (11.8) 88.6 (5.9)† 20.7 8.6 100
EIB10 (n ⴝ 33) 51.5 69.7 18.2 9.1 27.3 18.2 15.2 6.1 88.8 (11.4) 89.6 (6.1) 100 30.3 36.4†
EIB15 (n ⴝ 10) 70.0 70.0 30.0 20.0 28.1 20.0 10.0 10.0 90.6 (15.6) 90.6 (15.6) 100 100 50.0†
Abbreviations: AHR, airway hyperresponsiveness; EIB, exercise-induced bronchospasm; EIB10, 10% decrease in FEV1 from baseline at exercise test; EIB15, 15% decrease in FEV1 from baseline at exercise test; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. * Data are percentage of patients unless otherwise indicated. † P ⬍ .05.
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Table 2. Prevalence of AHR to Histamine, Wheezing, Asthma, Atopy, Rhinitis, and Dermatitis at Follow-up at the Age of 19 to 29 Years According to Presence of AHR to Histamine or EIB at Inclusion in 281 Individuals Without Asthma at the Age of 7 to 17 Years*
AHR to histamine Wheezing ever Exercise-induced wheezing ever Asthma ever Current asthma FEV1, mean (SD), % predicted FEV1/FVC, mean (SD), % Atopy† Rhinitis (ever) Dermatitis (ever)
No AHR or EIB (n ⴝ 202)
AHR (n ⴝ 58)
EIB10 (n ⴝ 33)
EIB15 (n ⴝ 10)
7.1‡ 12.4‡ 44.1 10.9‡ 5.0‡ 98.3 (11.4) 85.4 (5.9) 28.0 27.2§ 12.4
28.1‡ 43.1‡ 56.9§ 37.9‡ 22.4‡ 94.5 (10.2) 84.3 (6.9) 34.5 43.1§ 10.3
9.1 21.1 60.6§ 15.2 12.1 96.6 (11.7) 86.4 (6.6) 18.2 27.3 9.1
20.0 40.0 60.0 30.0 30.0§ 98.7 (9.5) 87.4 (7.6) 30.0 40.0 30.0
Abbreviations: AHR, airway hyperresponsiveness; EIB, exercise-induced bronchospasm; EIB10, 10% decrease in FEV1 from baseline at exercise test; EIB15, 15% decrease in FEV1 from baseline at exercise test; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. * Data are percentage of patients unless otherwise indicated. † Atopy is defined as a positive skin prick test result to at least 1 of the 10 aeroallergens in a standard test panel. ‡ P ⬍ .001. § P ⬍ .05.
with EIB15 had experienced asthma, as opposed to only 15% of participants with EIB10 (Table 2). Wheezing, as well as exercise-induced wheezing, was more commonly reported in participants with than without AHR to histamine and/or EIB10 or EIB15 (Table 2). At follow-up, rhinitis was reported by a higher number of participants with than without AHR to histamine (43% vs 27%), whereas a positive skin prick test result or dermatitis was not significantly more common in this group (Table 2). In a univariate regression analysis of the impact of different risk factors in participants with AHR to histamine or EIB10 or EIB15, a parental history of asthma, selfreported rhinitis and/or dermatitis, and ownership of furred pets in childhood increased the risk of subsequent asthma in adulthood in participants with AHR to histamine (Table
3). In a multivariate regression analysis, these factors remained statistically significant, indicating that they were independent predictors of asthma development (Table 4). The odds ratio for parental asthma doubled in the multivariate analysis, which could have been a result of covariation among the explanatory variables or a mediator effect among the explanatory variables on the effect of the single variable on the outcome. However, no statistically significant correlations were observed between the explanatory variables included in the multivariate analysis, and no effect modification was observed between the effect of any included variable and that of any other included variable on the outcome when testing for interactions. For participants with EIB10 and/or EIB15, no significant risk factors for asthma development were identified.
Table 3. Univariate Logistic Regression Analysis of Risk Factors for Current Asthma at the Age of 19 to 29 Years in Individuals With Asymptomatic AHR to Histamine and/or EIB10 at the Age of 7 to 17 Years* OR (95% CI) Risk Factor Parental asthma Parental allergy Pets in childhood Passive smoking in childhood Wheezing in childhood Atopy† Rhinitis Dermatitis Dermatitis and/or rhinitis
No AHR or EIB
AHR to histamine
EIB10
2.8 (0.7-11.3) 0.8 (0.7-1.1) 1.6 (0.4-5.9) 5.1 (0.6-41.6) 3.1 (0.6-16.2) 0.84 (0.2-4.1) 1.9 (0.4-9.7) 2.9 (0.3-26.5) 2.4 (0.6-9.9)
6.2 (1.2-32.8)‡ 2.5 (0.4-16.4) 4.4 (1.2-16.1)‡ 2.2 (0.6-9.2) 4.2 (0.8-24.0) 2.2 (0.6-8.2) 2.4 (0.5-11.8) 6.5 (1.0-43.8) 4.5 (1.2-17.6)‡
1.2 (0.5-2.9) 1.0 (0.4-2.8) 0.9 (0.4-2.0) 1.3 (0.6-2.8) 1.1 (0.3-0.9) 0.8 (0.3-1.9) 1.4 (0.5-3.8) 1.2 (0.3-5.5) 1.3 (0.5-3.3)
Abbreviations: AHR, airway hyperresponsiveness; CI, confidence interval; EIB10, 10% decrease in forced expiratory volume in 1 second from baseline at exercise test; OR, odds ratio. * Risk factors present at inclusion (age 7-17 years). † Atopy is defined as a positive skin prick test result to at least 1 of the 10 aeroallergens in a standard test panel. ‡ P ⬍ .05.
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Table 4. Multivariate Logistic Regression Analysis of Risk Factors for Current Asthma at the Age of 19 to 29 Years in Individuals With Asymptomatic AHR to Histamine at the Age of 7 to 17 Years Risk factor Parental asthma Pets in childhood Dermatitis and/or rhinitis
OR (95% CI) 12.6 (1.5-108.5)* 6.0 (1.2-19.6)* 2.2 (1.1-5.1)*
Abbreviations: AHR, airway hyperresponsiveness; CI, confidence interval; OR, odds ratio. * P ⬍ .05.
DISCUSSION AHR to histamine and EIB in asymptomatic children predicted the subsequent development of wheezing and clinical asthma in adulthood. The predictive value of AHR to histamine was, however, higher than that of EIB for the development of wheezing and asthma. In individuals with AHR to histamine, a parental history of asthma and ownership of furred pets in childhood and dermatitis and/or rhinitis in childhood significantly predicted the development of asthma in adulthood. Previous epidemiologic data have described a similar increased risk of development of asthma and wheezing in patients with AHR to histamine or EIB. Similar to our findings, Rasmussen at al3 described a significant but low predictive value (26%) of asymptomatic EIB in childhood for wheezing later in life. As mentioned, AHR to histamine seems to be a stronger predictor of subsequent asthma symptoms. We found that almost 60% of individuals with AHR to histamine later experienced exercise-induced wheezing. This finding is similar to what others have described: 67% of children with asymptomatic AHR to methacholine in the New Zealand cohort reported wheezing at the age of 26 years.12 EIB is presumably mediated through inflammatory cells in the airways, which may explain the higher specificity of EIB in diagnosing asthma. It is therefore surprising that EIB has a lower predictive value for asthma development than AHR to direct agents such as histamine, which do not require inflammation to be present. Several possible explanations exist for this finding, such as perception of bronchoconstriction, degree of inflammation, and presence of triggers. First, the present population was asymptomatic when tested, and it can be speculated that individuals with EIB have a lower perception of their bronchoconstriction than symptomatic patients (ie, they had mild asthma that they did not register and therefore was not reported at the first or last survey). Participants with EIB15 would normally be classified as having asthma, because the exercise test has a high specificity in symptomatic individuals, which supports the suggestion that these individuals are poor preceptors of their bronchoconstriction. Second, the inflammation in these asymptomatic individuals may have been milder than in the symptomatic patients and as such insufficient to cause symptoms of airway obstruction. In this context, airway inflammation has been shown to be milder in
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asymptomatic individuals compared with symptomatic individuals.13 Finally, the lack of reported asthma symptoms may be due to insufficient triggers, such as lack of exercise in sedentary people or lack of allergen exposure or respiratory irritants. Asymptomatic AHR represents a clinical problem. When asthma is clinically present, airway remodeling has often led to irreversible structural and functional changes.14 Prevention of the development of clinical asthma therefore remains relevant, and because asymptomatic AHR will in some cases predict asthma development, it could be used as an indication of preventive measures. Although it is true that many cases of clinical asthma occur in individuals without a prior history of AHR, our finding that AHR was present in more than 50% of our study participants who subsequently reported symptoms of asthma shows that AHR is not an infrequent predictor of asthma. Furthermore, asthma developed in approximately 40% of participants with AHR, indicating that these are individuals at high risk of developing asthma and accordingly a high impact of any effective preventive measures. Because asthma will not develop in all individuals with AHR, it is important to define risk factors for asthma in this particular group. We found that the simultaneous presence of atopic manifestation disorders such as rhinitis or dermatitis increased the risk of asthma in adulthood in those individuals who had a positive histamine test result in childhood. This finding supports the observations of others that atopic manifestations in individuals with AHR to direct agents are predictors of development of respiratory symptoms, possibly as an indication of active airway inflammation.4 Owning furred pets significantly increased the risk of developing asthma in individuals with AHR to histamine, suggesting that these individuals are particularly susceptible to the effect of allergen exposure and in keeping with the described association between AHR and atopy. We found a strong association between parental asthma in individuals with AHR and asthma in adulthood in the present study, suggesting that in individuals with a genetic predisposition to asthma, the prognostic significance of AHR is higher. AHR and atopy have been linked genetically to the same chromosome (5q), which furthermore supports this association.15 The impact of parental asthma was relatively lower in the univariate analysis compared with the multivariate analysis. We have analyzed all possible interactions between the explanatory variables or a mediator effect of any of these variables on the effect of any other variable on the outcome that may have caused this alteration. However, no significant first-order interactions were demonstrated. One of the possible explanations for the alteration in odds ratios and standard deviations from the univariate to the multivariate analysis could be an effect of the relatively low number of observations for each risk factor, particularly in the case of parental asthma. Our findings did however remain statistically significant in the multivariate analysis. Accordingly, we believe that our findings are substantial and that the factors found to
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be statistically associated with an increased risk of the development of asthma in individuals with AHR are indeed clinically relevant. Although we did not find an association between the presence of asymptomatic AHR and concomitant atopic manifestation in the present study, we have previously reported a significant association between AHR to histamine and a positive skin prick test result in the original sample of 527 individuals evaluated at the first survey.16 The lack of a similar finding in the present analysis is likely to be a result of the smaller sample size, arising from the fact that only 55% of the original sample was available for follow-up. Rhinitis developed more frequently in individuals with AHR to histamine, reflecting the findings of other epidemiologic surveys; Rasmussen et al12 found that asymptomatic AHR in childhood was associated with a higher level of IgE and eosinophils and a higher prevalence of a positive skin prick test result in adulthood. In conclusion, we have shown that asymptomatic children and adolescents who are hyperresponsive to histamine or exercise are at increased risk of developing asthma in adulthood and that this risk is further increased in those with a parental history of asthma, those with concomitant rhinitis or dermatitis, and those who owned furred pets in childhood. REFERENCES 1. Cockcroft DW. How best to measure airway responsiveness. Am J Respir Crit Care Med. 2001;163:1514 –1515. 2. Brusasco V, Crimi E, Pellegrino R. Airway hyperresponsiveness: not just a matter of airway inflammation. Thorax. 1998;53: 992–998. 3. Rasmussen F, Lambrechtsen J, Siersted HC, Hansen HS, Hansen NC. Asymptomatic bronchial hyperresponsiveness to exercise in childhood and the development of asthma related symptoms in young adulthood: the Odense Schoolchild Study. Thorax. 1999;54:587–589. 4. Toelle BG, Xuan W, Peat JK, Marks GB. Childhood factors that predict asthma in adulthood. Eur Respir J. 2004;23:66 –70. 5. Ferris BG Sr. American Thoracic Society Executive Committee: standardization project. Am Rev Respir Dis. 1978; 18:1–120. 6. US Department of Health, Education and Welfare. Proceedings of the First NHLBI Epidemiology Workshop. Washington, DC: US Dept of Health, Education and Welfare; 1971.
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7. Hopp RJ, Bewtra AK, Nair NM, et al. Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children. J Allergy Clin Immunol. 1984;74:154 –158. 8. Hopp RJ, Townley RG, Biwen RE, et al. The presence of airway reactivity before development of asthma. Am Rev Respir Dis. 1990;141:2– 8. 9. Cockcroft DW, Killian KN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7:235–243. 10. Juniper EF, Cockroft DW, Hargreave FE. Histamine and Methacholine Tests: Tidal Breathing Method, Laboratory Procedure and Standardization. Ottawa, Ontario: Canadian Thoracic Society; 1991. 11. Ulrik CS, Backer V. Increased bronchial responsiveness to exercise as a risk factor for symptomatic asthma: findings from a longitudinal population study of children and adolescents. Eur Respir J. 1996;9:1696 –1700. 12. Rasmussen F, Taylor DR, Flannery EM, et al. Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: a longitudinal population study. Pediatr Pulmonol. 2002;34:164 –171. 13. Boulet LP. Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma? Am J Respir Crit Care Med. 2003;167:371–378. 14. Boulet LP, Turcotte H, Laviolette M, et al. Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma influence of inhaled corticosteroids. Am J Respir Crit Care Med. 2000;162:1308 –1313. 15. Amelung PJ, Postma D, Panhuysen CI, Meyers DA, Bleecker ER. Susceptibility loci regulating total serum IgE levels, bronchial hyperresponsiveness, and clinical asthma map to chromosome 5q. Chest. 1997;111(6 suppl):77S–78S. 16. Backer V, Ulrik CS, Hansen KK, Laursen EM, Dirksen A, Bach-Mortensen N. Atopy and bronchial responsiveness in random population sample of 527 children and adolescents. Ann Allergy. 1992;69:116 –122. Requests for reprints should be addressed to: Celeste Porsbjerg, MD Respiratory Unit Department of Internal Medicine Bispebjerg Hospital Bispebjerg Bakke 23 2400 Copenhagen NV, Denmark E-mail:
[email protected]
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