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Asthma is associated with increased airway responsiveness (AR), but the age when this relationship becomes established is not clear. The present study tested the hypothesis that the association between increased AR and asthma is established after 1 month of age.To relate AR in infancy to asthma in childhood.As part of a birth cohort study, AR was determined at 1 (early infancy), 6 (mid-infancy), and 12 months of age (late infancy). At 11 years of age (childhood), AR and the presence of asthma symptoms were determined.Of the 253 study subjects enrolled, AR was determined in 202 in early infancy, 174 in mid-infancy, 147 in late infancy, and 176 in childhood. Increased AR in late infancy, but not in early or mid-infancy, was associated with increased wheeze at 11 years of age (P = 0.016). Increased AR in infancy persisted into childhood in association with male gender, early respiratory illness, and maternal smoking and asthma. Among the 116 subjects assessed in late infancy and childhood, recent wheeze was present in 35% of children with increased AR at both ages, 13% with increased AR in childhood only, 12% for those with increased AR in late infancy only, and 0% for those who did not have increased AR at either age (P = 0.023); the proportions of children with diagnosed asthma in the corresponding groups were 27, 20, 12, and 0% (P = 0.038).The association between increased infantile AR and childhood asthma emerges at the end of the first year of life.

Studies of airway responsiveness (AR) have typically used similar dose schedules of methacholine for adults and children despite large ranges in subject size. Reported declines in AR with increasing age in children could be due to maturational changes or to proportionately smaller doses of methacholine in taller (older) children. Other investigators have related both height and various measures of lung function to AR. We examined data related to AR in 471 children, aged 6 to 8 yr, from a birth cohort. Each child underwent spirometry followed by sequential challenge with five doses of methacholine, ranging from 0.025 to 25 mg/ml, given with a dosimeter. Continuous slope and end FEV(1)-change indexes of responsiveness were computed. Using stepwise regression modeling, we found no significant association between AR and either height or age after entering a variable reflecting asthma or wheezing. In contrast, we found that baseline measures of FVC, FEV(1)/FVC, and FEF(25-75%) were significantly related to AR after controlling for other variables (p = 0.001). However, when all three of the latter measures were added to models, FEF(25-75%) was most closely related to AR. We conclude that after control for other variables, FEF(25-75%) and FVC, but not height, are significantly related to methacholine responsiveness in children.

Bronchial responsiveness (BR) is an important risk factor for the development and outcome of asthma. This study assessed childhood risk factors for both the severity of BR in adulthood and either improvement or worsening of BR over time. Finally, we studied cross-sectional risk factors of BR in adulthood. Between 1966 and 1969, 119 allergic asthmatic children (5-14 yr of age) were studied. Of these, 101 (85%) subjects were reinvestigated at age 22-32 yr (visit 2), and at age 32-42 yr (visit 3). Spirometry, PC10 histamine, skin tests, blood eosinophils, and serum total IgE were measured and a questionnaire was used. Higher FEV1 values in childhood were associated with less severe BR at age 32-42 yr independent of other potential risk factors. Larger increases in FEV1 values both from visit 1 to 2 and from visit 2 to 3, a longer time interval from visit 1 to 3, and having pets in childhood were associated with less severe BR at age 32-42 yr. The same factors were found to be associated with less deterioration of BR from visit 2 to 3. In nonsmokers a higher IgE level at visit 2 was a risk factor for an increase in BR. At age 32-42 yr, a low level of lung function and the presence of asthma symptoms were associated with more severe BR, and older age and having pets were associated with less severe BR. IgE was related to more severe BR only in nonsmokers. Conclusions: A lower lung function in childhood and less improvement in FEV1 over time were associated with more severe BR in adulthood.

Bronchial responsiveness (BR) is an important risk factor for the development and outcome of asthma. This study assessed childhood risk factors for both the severity of BR in adulthood and either improvement or worsening of BR over time. Finally, we studied cross-sectional risk factors of BR in adulthood. Between 1966 and 1969, 119 allergic asthmatic children (5-14 yr of age) were studied. Of these, 101 (85%) subjects were reinvestigated at age 22-32 yr (visit 2), and at age 32-42 yr (visit 3). Spirometry, PC10 histamine, skin tests, blood eosinophils, and serum total IgE were measured and a questionnaire was used. Higher FEV1 values in childhood were associated with less severe BR at age 32-42 yr independent of other potential risk factors. Larger increases in FEV1 values both from visit 1 to 2 and from visit 2 to 3, a longer time interval from visit 1 to 3, and having pets in childhood were associated with less severe BR at age 32-42 yr. The same factors were found to be associated with less deterioration of BR from visit 2 to 3. In nonsmokers a higher IgE level at visit 2 was a risk factor for an increase in BR. At age 32-42 yr, a low level of lung function and the presence of asthma symptoms were associated with more severe BR, and older age and having pets were associated with less severe BR. IgE was related to more severe BR only in nonsmokers. Conclusions: A lower lung function in childhood and less improvement in FEV1 over time were associated with more severe BR in adulthood.

A study was undertaken in a number of rowhouses, some of which had had previous problems related to dampness and water leakage. The aim of the study was to assess the relation between exposure to airborne (1--3)-beta-D-glucan, a cell-wall substance in molds, and airways inflammation. The study involved 75 houses with indoor (1--3)-beta-D-glucan levels ranging from 0 to 19 ng/m3. Of 170 invited tenants, 129 (76%) participated in the study. A questionnaire relating to symptoms was used, and measurements were made of lung function and airway responsiveness. Myeloperoxidase (MPO), eosinophilic cationic protein (ECP), and C-reactive protein (CRP) were measured in serum. Atopy was determined with the Phadiatop test. The major findings were a relation between exposure to (1--3)- beta-D-glucan and an increased prevalence of atopy, a slightly increased amount of MPO, and a decrease in FEV1 over the number of years lived in the house. The results suggests the hypothesis that exposure to (1--3)-beta-D-glucan or molds indoors could be associated with signs of a non-specific inflammation.

The present study investigated the outcome of asthma in a population of 181 adult patients 13 to 44 yr of age (median, 24 yr) who were extensively tested between 1962 and 1970 and in whom asthma was diagnosed. When retested 25 yr later, 38 subjects (21%) did not show bronchial hyperresponsiveness (BHR)(PC20 > 16 mg/ml), 45 subjects (25%) showed a FEV(1) > 90% predicted, and 72 subjects (40%) did not report pulmonary symptoms. When absence of asthma was defined as no BHR, FEV(1) > 90% predicted, and the absence of pulmonary symptoms reported by the patient, 20 subjects (11%) were no longer considered asthmatic when retested. Absence of asthma after 25 yr was associated with a younger age and less severe airway obstruction at first testing, odds ratios (OR) being 0.36 for age/10 yr, and 1.42 for FEV(1)/height(2) (dl/m(2)). Absence of BHR was associated with a younger age, a higher FEV(1), and a shorter untreated period (years between onset of asthma symptoms and specialized treatment of the disease) at first testing, and a lower total serum IgE level (IU/L) at second testing (OR, 0.48 for age/10 yr; OR, 1.37 for FEV(1)/height(2); OR, 0.93 for untreated period; OR, 0.33 for log [IgE]). Neither sex nor atopy (one or more positive skin tests) were significant determinants of the outcome of both asthma and BHR. Our results suggest that in a substantial proportion of symptomatic asthmatics the disease improved, and that subsets may outgrow their asthma, even in adulthood. The data lend indirect support to the hypothesis that milder disease and earlier intervention are important for a beneficial outcome of asthma.

The cysteinyl leukotriene LTE(4) has been shown to induce airway eosinophilia in asthmatics in vivo. This phenomenon has not yet been reported for LTD(4). Hence, we examined the effect of inhaled LTD(4) and a control bronchoconstrictor agent, methacholine, on cell differentials in hypertonic saline-induced whole sputum samples of 12 nonsmoking atopic asthmatic subjects (three women, nine men; 21 to 29 yr of age; FEV(1), 74 to 120% pred; PC(20)FEV(1) methacholine

The cysteinyl leukotriene LTE(4) has been shown to induce airway eosinophilia in asthmatics in vivo. This phenomenon has not yet been reported for LTD(4). Hence, we examined the effect of inhaled LTD(4) and a control bronchoconstrictor agent, methacholine, on cell differentials in hypertonic saline-induced whole sputum samples of 12 nonsmoking atopic asthmatic subjects (three women, nine men; 21 to 29 yr of age; FEV(1), 74 to 120% pred; PC(20)FEV(1) methacholine

We investigated the coherence of bronchial hyperresponsiveness (BHR) and peak expiratory flow (PEF) variability in their relation to allergy markers and respiratory symptoms in 399 subjects (20-70 yr). Bronchial hyperresponsiveness to methacholine was defined by both the provocative dose causing a fall in FEV(1) of 20%, and the dose-response slope. PEF variability was determined as diurnal PEF variation (amplitude percent mean) and between-day PEF variation. Skin tests positivity, serum total IgE, and specific IgE (RAST) for house-dust mite (HDM), cat, timothy grass, and birch (''pollen'') were determined, as well as the number of peripheral blood eosinophils. Wheeze and nocturnal dyspnea were defined as asthma-like symptoms; dyspnea greater than or equal to grade 3, cough and phlegm as chronic obstructive pulmonary disease (COPD)-like symptoms. The reciprocal of the dose-response slope and PEF variability were significantly correlated (r = -0.39). Subjects with a positive skin test for HDM (odds ratio [OR] = 3.9), cat (OR = 8.3), or pollen (OR = 3.6), or specific IgE for HDM (OR = 2.3), cat (OR = 3.4), or pollen (OR = 1.9) had increased risk of BHR compared with the reference group (all p values

The influence of exogenous factors in the home on the circadian variation of airway obstruction has not been fully assessed in children with asthma. The aim of the present study was to investigate the contribution of exogenous stimuli to the degree of peak expiratory flow (PEF) variability during 24 h. Fifty-five children (33 boys and 22 girls; mean age, 9.3 +/- 1.7 yr) with symptoms of asthma, increased bronchial responsiveness, and a solitary allergy to house dust mite (HDM) participated. Their asthma symptoms were well-controlled for at least 4 mo with daily inhaled corticosteroids (ICS) and beta(2)-adrenergic drugs if needed. Symptoms, peripheral blood eosinophils, total IgE, and specific IgE to HDM were assessed. Spirometry and PC20 histamine were performed. PEF amplitudes during 24 h (highest minus lowest as a percentage of the day's mean value) were obtained at home during and 6 d after withdrawal of ICS. Dust samples were collected from the total area of the living rooms, bedrooms, mattresses (n = 25), and classrooms to obtain the HDM allergen (HDMA) exposure to Der p I and Der p II. Family smoking habits, presence of pets, and types of floor-covering were recorded on a checklist. Mean PEF amplitude did not increase after withdrawal of ICS, but absolute PEF values were significantly lower (p 0.05) at midnight and 4:00 A.M. Twenty-six children (47%) were exposed to environmental tobacco smoke (ETS), and 23 (42%) kept pets. Mattresses contained significantly higher amounts of HDMA compared with other locations. PEF amplitude after withdrawal of ICS was significantly higher in children exposed to ETS, a pet, or a high HDMA level in their mattress than in children who were not exposed (ETS: 29.7% [3.9 to 56.6] versus 19.4% [0.0 to 56.6], p

The present study was set up to investigate whether salmeterol in children with asthma already treated with inhaled corticosteroids (ICS) leads to a sustained bronchodilator effect and decreased bronchial responsiveness, both during the day and night. Furthermore, we investigated whether cessation of salmeterol leads to a rebound increase in bronchial responsiveness. Forty children with asthma (aged 7-15 yrs) using ICS participated in a randomized, double-blind, parallel study. They received either twice daily 50 mu g salmeterol or placebo. FEV(1) and provocative concentration of methacholine that caused a 20% fall in FEV(1) (PC20) were measured at 4:00 P.M, and 4:00 A.M. at baseline and after 16 wk. The same measurements were performed at 4:00 P.M. at 8 h after the first dose, and after 1 and 8 wk. After cessation of the study drug, FEV(1) and PC20 Were measured at 12 and 20 h and after 1 wk. Overall mean FEV(1) from 1 to 16 wk of treatment was significantly higher in the salmeterol group than in the placebo group (difference, 4.9 +/- 2.0%, p = 0.01). Evolution in time of FEV(1) did not differ significantly between the two groups (p = 0.09). Overall mean PC20 from 1 to 16 wk of treatment was not significantly higher with salmeterol than with placebo (difference, 0.7 +/- 0.4 doubling dose [DD] p = 0.07); evolution in time of PC20 did not differ significantly between the two groups (p = 0.58). The increase of PC20 8 h after the start of the study was significantly higher with salmeterol than with placebo (1.9 +/-:0.3 DD versus 0.7 +/- 0.3 DD, p

Methodologies used to assess airway responsiveness (AR) in children administer the same dosage schedule to all children despite the great range in the size of subjects. The aim of this study was to examine the hypothesis that the level of AR is size dependent within same-age cohorts and between different ages. Among a birth cohort of 1,037 New Zealand children participating in a longitudinal study, 818 had at least two measurements of airway responsiveness between ages 9 and 15 yr. Each child performed spirometry and a four-dose methacholine inhalation test. A continuous slope index of methacholine responsiveness was computed. AR slope indexes were analyzed using longitudinal methods, which included an indicator variable for subjects who reported having any wheeze. AR was lowest in both males and females in the upper quartile for height than those in the lower quartile, independently of age. AR tended to be higher (responded to lower concentrations of methacholine) in boys than girls and to decline with age among wheezers. The greater level of responsiveness in smaller or younger children could be explained by these individuals having received a dose of methacholine that was relatively large for their size.

Chronic exposure of rats to high concentrations of SO2 gas causes pathologic changes in airway similar to those seen in human chronic bronchitis. The purpose of this study was to examine the pulmonary mechanical correlates of these changes and to quantify the extent of mucous hypersecretion by measuring changes in mucous glycoproteins. Female Sprague-Dawley rats were exposed to 250 ppm SO2 gas, 5 h/d, 5 d/wk, for a period of 4 wk. Control rats were exposed to air only. On the day after the last SO2 exposure, rats were anesthetized, instrumented for the measurement of pulmonary resistance (RL) and dynamic compliance (Cdyn), and ventilated. Chronic SO2 exposure caused a small but significant increase in RL and decrease in Cdyn. Airway responsiveness to inhaled aerosolized methacholine was increased in SO2-exposed rats, as indicated by approximately 6.6- and 4.6-fold decreases respectively, in the doses of inhaled methacholine required to double RL or decrease Cdyn to 50% of baseline. SO2 exposure had no effect on the contractile response of the trachea measured in vitro. Tracheae and lungs from SO2-exposed animals exhibited 140 and 535% increases in measured neutral mucous glycoproteins, respectively, and 33 and 37% increases in acid glycoproteins. Our results indicate that this animal model of chronic bronchitis mimics the mucous hypersecretion, airway obstruction, and increased airway responsiveness observed in human bronchitis and may allow us to begin to probe their mechanistic basis.

The validity of peak expiratory flow (PEF) recordings and the sensitivity of PEF variability indices in asthma and asthma-like conditions were examined in an adolescent population. Recordings from 245 randomly selected subjects and from an additional 181 subjects reporting or considered at risk for developing asthma were analyzed. Subjects recorded PEF twice daily for 2 wk using Mini-Wright meters, completed a symptoms questionnaire, and were tested for airway responsiveness to methacholine. The first three recording days showed significant accumulation of lowest PEF values recorded (41%) and were excluded from further analysis. Among nine PEF variability indices, the Two-lowest%mean (the mean of the two lowest PEF values as a percentage of the period mean) had the best sensitivity for physician-diagnosed asthma (28%). The sensitivity of the methacholine dose-response slope (DRS) was 69%. Combining these indices, a sensitivity of 77% for diagnosed asthma was obtained. Among subjects with asthma-like symptoms but no diagnosis of asthma, 14% had increased Two-lowest%mean and the DRS was increased in 17%, but only 3% were identified by both tests. In conclusion, inhomogeneity of PEF data could be corrected by disregarding the first three recording days. PEF variability indices identified some diagnosed asthmatics, and particularly some symptomatic "nonasthmatics," not identified by the DRS, suggesting that the combined use of these indices might be helpful.

Increasing nonspecific airway responsiveness during aging may precede and predispose to the development of asthma in later life. Characteristics potentially related to longitudinal change in methacholine airway responsiveness were examined over a 3-yr follow-up interval among 435 middle-aged and older men. Initial and follow-up evaluation included spirometry, allergy skin testing with common aeroallergens, measurement of the serum concentration of total IgE, and blood cell counts (total leukocytes and eosinophils, basophils, and neutrophils as a percentage of total leukocytes). The initial values and annual rates of change of these characteristics were examined by multiple linear regression as potential predictors of annual change in methacholine dose-response slope. Annual change in basophil count was directly related to change in dose-response slope (p = 0.02). Initial values and annual rates of change of other cell counts, pulmonary function, allergy skin test reactivity, and serum total IgE concentration were not significantly related to change in dose-response slope. Cigarette smoking history was also not significantly related to longitudinal change in dose-response slope. These data suggest that inflammatory mechanisms involving the basophil may be important in the development of increasing nonspecific airway responsiveness during aging.

We present a review of specific health status measures, including symptoms, physical examination, and laboratory tests (exclusive of lung function tests), in terms of their suitability for assessing the presence and severity of asthma in epidemiologic and clinical research. We focus on the validity, reliability, and responsiveness to clinical intervention of these measures. Several adult questionnaires designed for epidemiologic research include questions on asthma and wheezing that have demonstrated repeatability and validity against concurrent measurements of nonspecific airway responsiveness. The International Union Against Tuberculosis Bronchial Symptoms Questionnaire was designed specifically to detect asthma and airway hyperresponsiveness in adult populations, and its reliability and validity have been well documented. A childhood questionnaire developed by Australian investigators has been demonstrated to provide information on asthma and wheezing that is reliable and valid against the criterion of concurrently measured nonspecific airway responsiveness. Although suitable for epidemiologic research, these questionnaires do not provide sufficient data on the severity of current asthma symptoms (aspects of which include intensity, duration, and frequency of symptoms) to be useful for clinical research involving subjects with established asthma. Many different methods of obtaining and analyzing symptom data have been used in clinical trials, but these have not received the methodologic scrutiny that allow the recommendation of a "best" approach for evaluating symptoms in clinical trials of interventions for asthma. The use of daily symptom diaries in short-term drug trials is common, but the optimal symptom-reporting interval for such studies has not been established. Similarly, a particular approach to integrating different symptoms (wheeze, dyspnea, cough, sputum) and the different aspects of these symptoms (intensity, duration, frequency) cannot be recommended on the basis of available data. Physical examination findings have little utility as asthma outcome measures because they may be normal between symptom episodes, they have relatively poor interobserver reliability, and they are relatively poor predictors of the outcome of emergency room visits for asthma. The finding of an elevated arterial PCO2 has utility as an indicator of a severe asthma attack, but arterial blood gas measurements have little other utility as asthma outcome measures. The chest radiograph is generally normal in patients with asthma and therefore not useful as an asthma outcome measure.(ABSTRACT TRUNCATED AT 400 WORDS)

The inbred mouse represents a powerful tool for dissecting both simple and complex traits. Genetic studies in the mouse should identify disease genes acting in the same biochemical pathway as in the human. Problems associated with genetic heterogeneity, inability to control environmental conditions, lack of an abundant supply of genetic markers, and ethical considerations regarding human genetic crosses are but some of the reasons to study airway responsiveness in the mouse. At present, only a handful of studies have shed light on the genetics of airway responsiveness; even fewer have sought to identify genetic loci that regulate this trait. It is clear that both genetic and environmental factors influence the asthma phenotype and that genetic background is an important consideration when interpreting segregation analysis data. The controversy over the specific mode of inheritance and number and location of quantitative trait loci (QTL) illustrates the need for additional studies. However, given that numerous candidate loci implicated in the pathogenesis of asthma map near QTLs identified in two recent studies, and given the considerable homology between the human and mouse genome, a targeted search for susceptibility genes is warranted in the human. Ideally, these regions will demonstrate linkage in humans. Thus, further work remains to be done to create detailed maps of the regions of linkage in the mouse, and to ultimately identify gene(s) that modify airway responsiveness. mice.

The present study investigated the outcome of asthma in a population of 181 adult patients 13 to 44 yr of age (median, 24 yr) who were extensively tested between 1962 and 1970 and in whom asthma was diagnosed. When retested 25 yr later, 38 subjects (21%) did not show bronchial hyperresponsiveness (BHR)(PC20 > 16 mg/ml), 45 subjects (25%) showed a FEV(1) > 90% predicted, and 72 subjects (40%) did not report pulmonary symptoms. When absence of asthma was defined as no BHR, FEV(1) > 90% predicted, and the absence of pulmonary symptoms reported by the patient, 20 subjects (11%) were no longer considered asthmatic when retested. Absence of asthma after 25 yr was associated with a younger age and less severe airway obstruction at first testing, odds ratios (OR) being 0.36 for age/10 yr, and 1.42 for FEV(1)/height(2) (dl/m(2)). Absence of BHR was associated with a younger age, a higher FEV(1), and a shorter untreated period (years between onset of asthma symptoms and specialized treatment of the disease) at first testing, and a lower total serum IgE level (IU/L) at second testing (OR, 0.48 for age/10 yr; OR, 1.37 for FEV(1)/height(2); OR, 0.93 for untreated period; OR, 0.33 for log [IgE]). Neither sex nor atopy (one or more positive skin tests) were significant determinants of the outcome of both asthma and BHR. Our results suggest that in a substantial proportion of symptomatic asthmatics the disease improved, and that subsets may outgrow their asthma, even in adulthood. The data lend indirect support to the hypothesis that milder disease and earlier intervention are important for a beneficial outcome of asthma.

To clarify whether asthma may be caused by fume from welding mild steel and to evaluate the possible strength of such an effect, we quantified airway responsiveness among young shipyard workers with different levels of fume exposure. Clinical investigation comprised a cross-sectional survey of 19- to 27-yr-old workers who were completing 3 to 9 yr of employment in various trades, and a control group of 15- to 17-yr-old school leavers who were applying for apprenticeships within the same trades. Both groups were subdivided into negligible-, ambient-, or high-exposure subgroups according to expected levels of fume exposure. Actual exposures were assessed in a parallel environmental survey. Participants were investigated by questionnaire, skin prick tests, spirometry, and methacholine tests. Complete data sets were obtained from 1,024 of the 1,070 eligible subjects (96%). Among the workers but not the school leaver controls, there was an increasing prevalence of positive methacholine tests across the exposure subgroups-negligible 37%, ambient 44%, high 49% (p < 0.05). Regression analyses showed that in males after allowing for the effects of atopy, current smoking, and age, the estimated geometric mean level of airway responsiveness of regular welders was twice that of workers with negligible exposure after 5 yr of work. This implies that fume exposure may have been critical in causing asthma in about 1% of the welders. A lesser effect (though not significantly so) was noted among the workers with ambient exposure.

Each of these effector systems has the capacity to initiate airway obstruction or alter airway responsiveness in asthma. It is likely that they act in concert in certain asthmatic settings. Further basic and applied research will define their relative roles in asthma.

Viruses provoke symptoms of wheezing in many patients with asthma. Furthermore, there is evidence that viruses increase airway responsiveness in non-asthma patients. The mechanisms involved in these reactions are not clearly established, but evidence suggests that the ability of viruses to promote this bronchial responsiveness may be related to an upregulation of the allergic inflammatory reaction. This would explain why patients may be more prone to have a late asthmatic reaction.

Studies have suggested that airway responsiveness declines with maturation; however, studies comparing infants, children, and adults are confounded by differences in size as well as maturation. Therefore, to determine whether maturation has a significant affect on airway responsiveness, we compared normal female children (n = 9; mean age = 13.6 yr) and adults (n = 7; mean age = 42.4 yr) who were matched for body size. Bronchial challenge tests were performed with increasing methacholine concentrations to a maximum of 30 mg/ml. At baseline, there were no significant differences between the two groups in lung volumes (TGV, RV, TLC) or flow-volume curves (FEV1, average forced expiratory flow rate between 25% and 75% of the vital capacity [FEF25-75], FVC). All subjects but one adolescent completed the challenge (30 mg/ml). The children had a greater percentage decline from baseline in FEV1 than the adults (17 versus 7%, p0.03). The percentage decline in FEF25-75 was greater for the children than for the adults, but the difference was not statistically significant (35 versus 20%, p0.10). Compared with the children, the adults more often demonstrated a plateau in their dose-response curves for FEV1 (22 versus 86%) and for FEF25-75 (33 versus 100%). We conclude that normal female children have a greater airway responsiveness to inhaled methacholine than do adults, and that this difference is not related to baseline lung size, airway caliber, or delivered methacholine dose.