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Home mattresses of 24 asthmatic children with house dust mite allergy were sprayed with either benzyl-benzoate foam or placebo in a double blind fashion, 10 days before the children left the residential house for asthmatic children Istituto Pio XII (located in the Italian Alps in an environment free of mites) and went back to their own home for the Christmas and Easter holidays. A further group of 8 children, whose mattresses received no treatment, was kept as an absolute control. Two days after spraying, benzyl-benzoate or placebo were vacuumed from the mattresses. Acarex test was performed immediately before spraying and at the end of each holiday period of 20 and 10 days, respectively. Bronchial hyperreactivity as well as serum and nasal secretory specific IgE for Dermatophagoides pteronyssinus were assessed in all children immediately before leaving and within 48 hr after returning to the residential house. The results of the study show that sprayed benzyl-benzoate foam was no more effective than placebo in reducing the level of house dust mite recovered from patients' mattresses, or in reducing bronchial hyperreactivity and IgE concentration in serum and nasal secretions.

How are the serum concentration of eosinophil cationic protein (S-ECP) and the blood eosinophil count (B-Eos) related to symptoms of asthma, allergy, and bronchial hyperresponsiveness (BHR)? We measured S-ECP, B-Eos, and total and specific IgE in serum in blood samples from 699 randomly selected persons 20-44 years old. They also underwent a structured interview, spirometry, a methacholine provocation test, and skin prick tests as part of the European Community Respiratory Health Survey. B-Eos and S-ECP were found to be closely related to asthma symptom score (P < 0.001), total IgE (P < 0.001), and BHR (P < 0.001). On the basis of the results, the subjects were divided into four groups: healthy controls, patients with allergic rhinitis, patients with nonallergic asthma, and patients with allergic asthma. There were significant differences in both B-Eos and S-ECP among the groups (P < 0.001), the highest values being found in the allergic asthma group. B-Eos and S-ECP each had an additive value in predicting the occurrence of asthma. Among persons with high concentrations of both variables, asthma was eight times more common than in those with low concentrations. Allergy and BHR were also found to be independently related to B-Eos and S-ECP levels. Furthermore, both B-Eos and S-ECP showed good correlation to subjective and objective measures of asthma activity. We conclude that both B-Eos and S-ECP and their interrelationship may be of value in assessing the activity of asthma. However, their role in disease management was not established in this cross-sectional study.

Most data about the course of occupational asthma after removal from exposure are based upon the longitudinal assessment of employees exposed to substances inducing late asthmatic reactions in bronchial provocation tests. It was the aim of this study to describe the course of immediate-type occupational asthma after allergen avoidance. Twenty-four platinum refinery workers were examined on two occasions. All subjects reported work-related asthma while they worked in the refinery department. The diagnosis of platinum salt asthma was established by a positive bronchial challenge test with hexachloroplatinic acid in each case. Eleven of the 24 subjects were still exposed to platinum salts at the time of the first investigation, but all had been removed from exposure for 19 mo (1 to 77) on the second investigation. Asthma was still reported by 17 subjects, and all but two showed bronchial hyperresponsiveness (PC50SGaw < 8 mg/ml) on the second investigation. Bronchial responsiveness to methacholine, skin reactivity, and bronchial responsiveness to platinum salt, as well as FEV1, did not change between assessments. Total serum IgE decreased from 126 to 103 U/ml (p < 0.005). Analysis of variance showed no association of the individual differences in PC50 (methacholine) between both investigations with smoking, time from the onset of symptoms to removal, time from removal to the first or second investigation, skin sensitization to environmental allergens, or total IgE. We conclude that both nonspecific and specific bronchial responsiveness do not decrease after removal from exposure in immediate-type asthma caused by platinum salts.

Methacholine bronchoprovocation challenge testing was successfully completed in 5,662 participants (3,556 men and 2,106 women) at the time they were randomized into the Lung Health Study, a multicenter trial designed to evaluate early intervention in chronic obstructive pulmonary disease (COPD). All participants were smokers between the ages of 35 and 60 yr who had mild COPD. The male:female prevalence of a positive challenge (PC20FEV1) was 25%:48% and 63%:87% at a PC20FEV1 of < or = 5 mg/ml (AHR5) and < or = 25 mg/ml (AHR25), respectively. This analysis explores these marked gender differences in airway hyperresponsiveness (AHR). Relative risks (RR) for predictors of AHR and the 95% confidence intervals (95% CI) were estimated using semiparametric Cox proportional-hazards models. The initial model controlled for age, gender, smoking history, height, and weight. The RR (95% CI) for female gender was 1.75 (1.60, 1.92). When the measured baseline FEV1 was added to the model as a surrogate for airway caliber, the RR for female gender decreased to 1.06 (0.96, 1.18). Thus, in this population of middle-aged smokers with mild COPD, the high prevalence of AHR appears to be associated with a decrease in airway caliber. The higher prevalence of AHR noted in women is due to their having a smaller airway caliber than their male counterparts.

Pollen is rarely investigated as a cause of winter respiratory symptoms. Infectious coryza and asthma are particularly common during winter, and it has been shown that environmental antigens can cause at least some cases in Paris. Recent experimental data from Calhoun et al. (1991) indicate that pollen may act synergistically with viral respiratory infections, which are particularly prevalent in winter. In the present study, we investigated, in 130 consecutive patients presenting with winter aggravation of asthma or rhinitis, winter pollinosis by skin test, radioallergosorbent test (RAST), and specific endonasal challenge test. Totals of 35, 24, and 21 patients reacted positively in skin, RAST (> 0.70 PRU/ml), and endonasal tests, respectively. Clinical features during the season established the diagnosis of winter pollinosis in 20 cases; it was due to alder pollen in 10 patients and hazel pollen in 12. The positive predictive value of the skin test was only 0.57, as compared with 0.86 for the specific endonasal test, which had a negative predictive value of 1. Our results indicate that hazel and alder pollens should be prick-tested for more often as causes of winter respiratory symptoms in Paris, even if similar manifestations were absent during previous winters, were previously present during spring or summer, or were both absent in previous winters and present in spring or summer.

Hospital admission rates for asthma in the 5 to 14 yr age group are three times higher in Fiji Indians than in Melanesian Fijians. Conversely, admission rates for pneumonia are three times higher for Fijians than Indians. To determine the prevalence of respiratory symptoms, bronchial hyperresponsiveness, and atopy, a questionnaire in three languages was distributed to 2,173 Suva City school children (mean age 9.6 yr), half of whom were sampled for histamine inhalation and skin-prick allergen tests. Prevalence of wheeze in the previous 12 mo was identical in both ethnic groups (20.6%). Productive cough was more common in Fijians (29%) than Indians (17%, p < 0.0001). Bronchial hyperresponsiveness was twice as common in Indians (30%) as Fijians (15%), relative risk 2.1 (95% confidence interval [CI]: 1.5 to 2.8), p < 0.0001. The combination of current wheeze and bronchial hyperresponsiveness was found in nearly three times as many Indian children (11.3%) as Fijians (4.0%), and the mean bronchial dose-response slope to histamine was steeper in Indians than Fijians. Prevalence of atopy was similar in Fijians (36%) and Indians (38%). Wheeze was significantly associated with atopy and a steeper dose-response slope to histamine, but productive cough was not. Indians may have more severe asthma than Fijians due to genetic or environmental factors acting independently of atopy. The higher prevalence of productive cough in Fijians is consistent with a greater burden of respiratory infection, and is associated with domestic crowding.

Objective: To investigate whether prevalence of asthma in children increased in 10 years., Design: Serial cross sectional studies of two populations of children by means of standard protocol., Setting: Two towns in New South Wales: Belmont (coastal and humid) and Wagga Wagga (inland and dry)., Subjects: Children aged 8-10 years: 718 in Belmont and 769 in Wagga Wagga in 1982; 873 in Belmont and 795 in Wagga Wagga in 1992., Main Outcome Measures: History of respiratory illness recorded by parents in self administered questionnaire; airway hyperresponsiveness by histamine inhalation test; atopy by skin prick tests; counts of house dust mites in domestic dust., Results: Prevalence of wheeze in previous 12 months increased in Belmont, from 10.4% (75/718) in 1982 to 27.6% (240/873) in 1992 (P < 0.001), and in Wagga Wagga, from 15.5% (119/769) to 23.1% (183/795) (P < 0.001). The prevalence of airway hyperresponsiveness increased twofold in Belmont to 19.8% (173/873) (P < 0.001) and 1.4-fold in Wagga Wagga to 18.1% (P < 0.05). The prevalence of airway hyperresponsiveness increased mainly in atopic children only, but the prevalence of atopy was unchanged (about 28.5% in Belmont and about 32.5% in Wagga Wagga). Numbers of house dust mites increased 5.5-fold in Belmont and 4.5-fold in Wagga Wagga., Conclusions: We suggest that exposure to higher allergen levels has increased airway abnormalities in atopic children or that mechanisms that protected airways of earlier generations of children have been altered by new environmental factors.

The aim of this study was to investigate the association between headache and asthma, bronchodilators and atopy in school children. A cross-sectional survey of all primary school children was conducted in two towns near Newcastle, New South Wales, Australia; one in the vicinity of two coal-fired power stations, the other free of outdoor industrial air pollution. The main outcome measures were frequent headache, wheezing, bronchial reactivity, use of bronchodilators and atopy. Eight hundred and fifty-one primary school children aged 5-12 years participated (92% response rate). Twenty-three per cent of the children were reported to have had a history of frequent headache. Crude odds ratios indicated that the odds of frequent headache was significantly higher in children with asthma and atopy and where there was a smoker in the home, but that there was no association between frequent headache and use of bronchodilators or the sex of the child or socio-economic status measured as father's occupation. Stepwise logistic regression with frequent headache as the outcome of interest showed that, after adjusting for age and smoking in the home, the odds ratio for asthma (defined as current wheeze) was 3.24 (95% confidence interval [CI] 2.19-4.77). The similarly adjusted odds ratio for asthma defined as bronchial hyperreactivity (BHR) was 1.60 (95% CI 1.09-2.37). Atopy was not statistically significantly associated with headache for either model. Asthma (defined as wheeze or BHR) is an independent risk factor for frequent headache. The relationship between headache and asthma is an association with bronchial hyperresponsiveness rather than atopy.

We studied the effects of reduced allergen exposure on bronchial hypereactivity (BHR) in two groups of asthmatic children allergic to house dust mites (HDM) living at high altitude for 9 continuous mo. In the first group the serum levels of total and HDM-specific IgE showed significant decreases after 3 mo (p < 0.001 and p < 0.02, respectively) and after 9 mo (p < 0.001). Three months after returning home the total IgE levels had increased significantly (p < 0.001). The mean percentage fall in peak expiratory flow after exercise testing improved after 3 and 9 mo (p < 0.05), but it had deteriorated after 3 mo at home (p < 0.01). The methacholine PD20-FEV1 increased after 3 mo (p = 0.001) and further after 9 mo (p < 0.001), with a decrease after the 3-mo period at sea level (p = 0.01). In the second cohort there was a significant increase in HDM PD20-FEV1 after 6 and 9 mo (p < 0.001), with a slight decrease of magnitude of the allergen-induced late reaction. Histamine PD20-FEV1 significantly increased after 6 and 9 mo at high altitude, particularly in the challenges performed after the HDM bronchial provocation (p < 0.01). Our data demonstrate that allergen avoidance in asthmatic children not only decreases nonspecific BHR but also decreases allergen sensitivity, late allergen-induced bronchial reactions, and enhancement of BHR by allergen challenge.

Both epidemiologic and experimental evidence suggest that a high dietary sodium intake may increase airway responsiveness, but no adequate explanation exists of how changes in sodium intake might lead to increased responsiveness. This investigation was carried out to study dietary sodium intake and airway response to methacholine in relation to cellular sodium transport in 52 young men. Airway response to methacholine was associated with urinary sodium excretion when subjects were on normal sodium intake. Airway responsiveness in patients with mild asthma correlated with the furosemide-insensitive influx of sodium into peripheral leukocytes stimulated by autologous serum, but there was no relation between this influx and 24-h urinary sodium excretion. In a separate investigation, serum from subjects with increased airway responsiveness caused an increase in the sodium influx and sodium content of leukocytes from nonatopic subjects. The magnitude of the furosemide-insensitive, serum stimulated influx was related to the degree of airway responsiveness of the serum donor, as was the increase in intracellular sodium content. Neither was related to the 24-h urinary sodium excretion of the donor. Patients with airway hyperresponsiveness have an increased sodium influx into cells stimulated by a serum-borne factor. This is independent of the effect of added dietary sodium on airway responsiveness.

This study evaluated the prevalence of increased bronchial responsiveness (BR) in children living in two areas with different air pollution levels. A total of 1,215 methacholine challenge tests were performed among a random sample of primary schoolchildren in an industrial town polluted by oil-fired thermoelectric power plants and in a rural area chosen as a control. The two groups showed similar lung function data (forced vital capacity [FVC] and forced expiratory volume in 1 s [FEV1.0]) and prevalence of positive prick tests to common aeroallergens. All children responding with a 20% drop in FEV1.0 to a methacholine concentration < or = 64 mg/ml, "all responders" (PC20FEV1.0 < or = 64 mg/ml), and the subgroup of "strong responders" (PC20FEV1.0 < or = 4 mg/ml) were compared separately with "nonresponders" (PC20FEV1.0 > 64 mg/ml), calculating odds ratios (ORs). There were more "all responders" (57.2% versus 41.4%) and "strong responders" (20.0% versus 14.8%) among subjects living in the industrial area; the excess remained when several potential confounders were taken into account ("all responders": OR = 2.0, 95% confidence interval [95% CI] = 1.5-2.6; "strong responders": OR = 1.9, 95% CI = 1.3-2.8), and it was even more pronounced among girls. When the effect of clinical predictors of increased airways responsiveness (history of asthma, allergic rhinitis, baseline airways caliber, skin reactivity, recent respiratory infection) was considered through multiple logistic regression, the odds ratios associated with living in the industrial area were still significantly increased in girls. The cross-sectional approach and the lack of individual exposure data limit the interpretation of the findings.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to assess the role of genetic factors and environmental influences in bronchial responsiveness, we studied the airway response to an inhaled bronchodilator in 66 nonasthmatic parents (age, 30.9 +/- 5.9 years) of infants with bronchiolitis (group 1). It was a placebo-controlled double-blind study. A control group (group 2) of healthy parents of infants who did not have bronchiolitis also were investigated with the test of bronchodilator response. All subjects showed normal expiratory airflow and lung volumes (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and mean forced expiratory flow during the middle half of FVC [FEF25-75%] > 80 percent of predicted) at baseline forced expiratory maneuver. In 16 (24.2 percent) subjects of group 1, there was significant increase in at least one parameter after salbutamol administration, but not after placebo inhalation, with respect to baseline levels. Furthermore, no significant changes in FVC, FEV1, or FEF25-75% values were found in group 2. In conclusion, this study confirms that parents of infants with bronchiolitis have an enhanced airway responsiveness, greater than control parents. Further studies are needed to assess whether one may infer the outcome of infants with bronchiolitis from this characteristic in their parents.

Two thousand eight hundred and forty one subjects, aged 8-73 yrs, took part in the second cross-sectional survey in the Po River Delta area: among them, a subsample of currently employed people, aged 14-71 yrs, was chosen to establish the relationship between occupational exposure to dusts, chemicals or gases and respiratory symptoms, lung function and bronchial reactivity. Each subject filled out the Italian National Research Council (CNR) standardized questionnaire concerning respiratory symptoms, diseases and risk factors. A variable proportion of subjects performed acceptable forced and slow vital capacity manoeuvres, diffusing capacity of carbon monoxide and bronchial challenge test to methacholine. Occupational exposure appeared to be related to prevalence rate of respiratory symptoms (wheeze, dyspnoea, presence of at least one respiratory symptom) and bronchial asthma. Consistent effects on lung function were not evident. With respect to the bronchial challenge test, using the measurement of the provocative dose producing a 20% fall in forced expiratory volume in one second (PD20) a significantly higher percentage of hyperreactive subjects was found among ex-smoker exposed men; a borderline higher percentage of hyperreactive subjects was also found in non-smoker exposed women. The study findings support the suggestion that occupational exposure may play a role in the development of airway obstructive diseases.

The German reunification offers a unique opportunity to study the impact of environmental factors on the development of childhood respiratory and allergic disorders in ethnically similar populations. We investigated the prevalence of asthma, hay fever, atopy, and bronchial hyperresponsiveness (BHR) in 9- to 11-year old children in West Germany (n = 5,030) and East Germany (n = 2,623). A self-administered questionnaire was distributed to the parents. Children underwent cold air challenge and allergy skin prick tests. Atopic sensitization was considerably more frequent in West German children than in their peers in East Germany (36.7% versus 18.2%; odds ratio [OR] = 2.6, p < 0.0001). The prevalence of current asthma and hay fever was significantly higher in West Germany when compared with that in East Germany (5.9% versus 3.9%; OR = 1.5, p < 0.0001 and 8.6% versus 2.7%; OR = 3.4, p < 0.0001, respectively). Bronchitis, however, was more prevalent in East Germany than in the western part of the country. The prevalence of BHR as assessed by cold air challenge was higher in West Germany compared with that in East Germany (8.3% versus 5.5%, OR = 1.6, p < 0.001). Logistic regression showed that the West German study area was no longer a significant independent determinant of asthma once sensitization to mites, cats, and pollen was taken into account. We conclude that sensitization to aeroallergens is strikingly more frequent in West Germany than in East Germany and this may explain the differences in the prevalence of asthma and hay fever between the two parts of the country.

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.

The effect of passive smoking on the degree of nonspecific bronchial responsiveness (BR) in children was evaluated. In a cross-sectional survey of primary school children (7 to 11 yr) in Latium (Italy), a total of 1,215 methacholine challenge tests was performed. The children were divided into nonresponders (PC20 FEV1 > 64 mg/ml) and responders (PC20 FEV1 < or = 64 mg/ml), the latter including a subgroup of strong responders (PC20 FEV1 < or = 4.0 mg/ml). The role of passive smoking exposure was analyzed through logistic regression models. Higher odds ratios were found among girls (for strong responders: maternal smoking, OR 2.92; paternal smoking, OR 2.59); moreover, among girls there was a dose-response relationship with the number of cigarettes smoked by the mother. An effect modification was also detected for father's education and household crowding: maternal and paternal smoking were strong predictors of bronchial hyperresponsiveness in families in which the head was less educated and in overcrowded houses. The results were confirmed using a continuous index of BR (slope) and after adjustment for baseline airway caliber. We suggest that the effect of parental smoking on children's bronchial responsiveness is detectable when the conditions for a higher exposure level at home are met; females seem to be more susceptible.

A review is made of the principal themes that are discussed in this supplement of the Revue des Maladies Respiratoires. Three important questions on bronchial hyperresponsiveness, a key feature of asthma, are raised: 1) the clinical usefulness of its assessment, mostly in the atypical forms of asthma and in occupational asthma and, less so, to estimate the severity of asthma; data derived from the Bayesian analysis lead to the conclusion that it is a test which is better for excluding rather than for confirming asthma; in an epidemiological setting, the assessment of bronchial responsiveness should be carried out to assess both host factors and the effect of environmental exposure; 2) the method of assessment which should take into account the stimulus, be it pharmacological or not, the physiological index used to assess the response and the mode of expression of results; 3) finally, the mechanisms of bronchial responsiveness are probably multiple as examined in different chapters of this supplement.

First used to evaluate individuals with symptoms suggestive of asthma, the assessment of bronchial hyperresponsiveness is now commonly used in epidemiological studies, available methods being reproducible and portable. This chapter defines how to assess bronchial hyperresponsiveness in epidemiological studies, which factors need to be considered, what is the prevalence in different populations and finally what are the indications for measuring bronchial hyperresponsiveness in epidemiological studies.

The outcome after 25 yr was studied for three groups of children classified in a random community survey in 1964 as having asthma (121 subjects), wheeze in the presence of infection (167 subjects), or no respiratory symptoms (167 comparison subjects). Approximately 80% of the subjects in each group, now aged 34 to 40 yr, were successfully traced. Current symptoms and smoking habit were recorded by questionnaire, and ventilatory function, peak flow variability, and bronchial reactivity to inhaled methacholine were measured. Subjects who had asthma in childhood were more likely to wheeze (odds ratio [OR] 14.4) or produce phlegm (OR 3.3) than comparison subjects. They also had significantly lower FEV1 values and greater bronchial reactivity than comparison subjects. Adult FEV1 correlated with childhood FEV1 (both expressed as % of predicted) (r = 0.44, p < 0.01). The prognosis for those children who were classed as having wheeze in the presence of infection in 1964 was better than for those who had asthma. Although they also were more likely to report wheeze (OR 3.8) or phlegm (OR 4.4) than comparison subjects, the wheezy symptoms were unlikely to interfere with activities and the ventilatory function and bronchial reactivity to methacholine did not differ from those of comparison subjects. Smokers were more likely to report wheeze (OR 2.0), cough (OR 7.2), and phlegm (OR 3.1) than never-smokers, and current smokers with current wheezy symptoms had significantly reduced FEV1 values, although smoking was not associated with increased methacholine reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

The various definitions that are proposed for bronchial hyper-responsiveness (BH) are discussed. The semantic problems related to these definitions are presented: 1) the translation of bronchial hyperresponsiveness into French can vary; 2) BH is not synonymous of abnormal contraction of airway smooth muscle; 3) there is also some confusion of BH with the clinical status of asthma, which is excessive. The authors also review the difficulties related to the purely operational character of the definition itself: 1) BH has a continuous distribution in a general population; 2) BH can be expressed by various indices; 3) stimuli to reveal BH are various; 4) there are various types of BH related to the causal conditions; 5) there are different sites of BH within the airways. The authors also review the historical background of BH with some emphasis on the contribution of French-speaking research workers.

Although generally associated with asthma, bronchial hyper-responsiveness has been observed in several clinical situations. Indeed, it has been clearly shown that patients with allergic rhinitis exhibit frequently bronchial hyperresponsiveness. The latter may be an important factor in the development of chronic airway obstruction. Airway hyperresponsiveness to direct bronchoconstrictors, histamine and metacholine, is seen also in subjects with chronic airflow limitation. Several lines of reasoning suggest that this may be different than the airway hyperresponsiveness seen in asthmatics and may predominantly relate to the degree of airflow obstruction. Consequently, in the presence of resting airflow obstruction, histamine and metacholine tests are difficult to interpret vis-a-vis a diagnosis of asthma. Some studies suggest accelerated decline of lung function in subjects with chronic airflow limitation and airway hyperresponsiveness. In interstitial lung disease preliminary data form subjects with lung diseases localized to the pulmonary interstitium suggest no (or very little) tendency to airway hyperresponsiveness. However, more data are necessary. Subjects with bilateral lung transplantation appear to develop mild, generally asymptomatic airway hyperresponsiveness which has been suggested to be due to cholinergic denervation hyper-sensitivity. Finally, asthmatics and nonasthmatics both may develop increased degrees of airway responsiveness following viral respiratory tract infections. Virus-induced airway inflammation is likely important in the pathogenesis of asthma in some subjects.

The relationship between bronchial responsiveness and the results of a skin prick test was studied in 527 children and adolescents from Copenhagen. All participants completed a questionnaire concerning birth weight, breastfeeding, month of birth, month of examination, allergic symptoms in themselves or their parents. Furthermore, skin prick test reactivity to nine common aero-allergens, lung function, serum IgE, and bronchial responsiveness to histamine and exercise were measured. A total of 158 (30%) subjects showed signs of allergy (defined as a positive reaction to the skin prick test), of whom 53 (10%) subjects had positive skin reactivity and 105 subjects had moderate skin reactivity; 366 (70%) subjects had no signs of allergic disease as measured by the pride test. The most important marker for the degree of bronchial responsiveness was asthma (p < 0.001), month of examination (p < 0.01) and allergy (skin reactivity to one or more allergens) (p < 0.05). Furthermore, the degree of bronchial responsiveness to inhaled histamine was significantly related to a history of asthma in two first degree relatives (p < 0.01) and the skin reactivity to house-dust mites (p < 0.01), whereas the degree of bronchial responsiveness to exercise was significantly associated with the level of serum IgE (p < 0.05), month of birth (p < 0.001) and birth weight (p < 0.05). In conclusion, allergy is an important risk factor for the presence of increased degree of bronchial responsiveness to inhaled histamine and to exercise.

While airway hyperresponsiveness is usually associated with a diagnosis of asthma or symptoms of wheezing, some individuals with rhinitis show airway hyperresponsiveness as do some with no symptoms whatsoever. We have studied the correlations between symptoms, airway hyperresponsiveness and atopy as determined by skin-prick tests in a cohort of New Zealand children. A total of 662 members of a birth cohort were studied at age 13 years using a respiratory questionnaire, skin-prick tests to 11 common allergens, and an abbreviated validated methacholine challenge test to determine airway responsiveness. Airway hyperresponsiveness (methacholine PC20 FEV1 < or = 8 mg/ml) was strongly correlated with reported asthma and current wheezing (P<0.0001) and also with atopy, especially to house dust mite and cat (P<0.0001). As weal size for both house dust mite and cat increased, so did the proportion of children with airway hyperresponsiveness. All children with diagnosed asthma and airway hyperresponsiveness were atopic. Skin-test reactions to house dust mite and cat were strongly correlated with any degree of measurable airway responsiveness (PC20 FEV1 < or = 25 mg/ml) in children with rhinitis (P<0.00001), and remained significantly correlated even in children without current asthma, without asthma ever and without rhinitis (P<0.001). Atopy is a major determinant of airway hyperresponsiveness in children, not only in those with reported histories of asthma and wheezing, but also in the absence of any history suggesting asthma and rhinitis.

The relation of house dust mite allergen levels to asthma and allergy was examined in two population samples of children aged 8-11 years in northern New South Wales. We studied 805 children in Lismore (a hot, humid, coastal region) and 770 in Moree/Narrabri (a hot, dry inland region). Respiratory symptoms were measured by questionnaire, bronchial hyperresponsiveness (BHR) by histamine inhalation test, and allergy by skin-prick tests. Current asthma was defined as the presence of both wheeze in last 12 months and BHR. Der p I levels were measured in dust from the bed and floors in the homes of 57 randomly selected children in the coastal region and of 74 inland children. Der p I levels were significantly higher by the coast (83.0 vs 11.2 microg/g, P < 0.001). House dust mite sensitivity was of similar prevalence in both regions (28.6 vs 26.4%, n.s.) but Alternaria sensitivity was higher inland (4.0 vs 15.2% P<0.001). Bronchial responsiveness was more severe in coastal children sensitized to house dust mites and in inland children who were sensitized to Alternaria. The adjusted odds ratios for current asthma in children sensitized to house dust mites were 21.3 (95% CI 10.5, 43.2) by the coast and 2.7 (95% CI 1.3, 5.4) inland, and in children sensitized to Alternaria were 3.4 (95% CI 1.3, 9.1) in the coastal region and 5.6 (95% CI 3.1, 10.1 inland. These studies suggest that high house dust mite allergen levels in a humid, subtropical region act to significantly increase bronchial responsiveness in sensitized children, and that Alternaria allergens have a similar but less potent action in a dry, rural region.

Although poorly reproducible spirometric tests, "test failures," are associated with respiratory morbidity, it is not clear what causes them. Bronchial responsiveness was examined in relation to test failure for forced expiratory volume in 1 s (FEV1.0) (1979 definition of the American Thoracic Society) in 249 bakers, 165 chemical industry workers, and 204 office workers. The first two groups were studied by the same methods and were combined. Test failure was observed in 4%, and for 38% the provocative dose of inhaled methacholine causing a 20% fall in FEV1.0 relative to FEV1.0 after the inhalation of normal saline (PD20) was < or = 120 mumol (7% with a PD20 of < or = 8 mumol). Test failure was not related to the level of PD20. Of the office workers, 3% had test failure, 11% a PD20 of < or = 8 mumol of histamine, and no significant relation was observed. The study does not exclude the possibility that bronchial responsiveness might be related to test failure in patients with airway disease or that a clearer relation might be demonstrable in a larger study, but it does suggest that it is not a major determinant of test failure.

Long-term variability of bronchial responsiveness has been studied in a random population sample of adults. During a follow-up period of 18 yr, 2,216 subjects contributed 5,012 observations to the analyses. Each subject could have as many as seven observations. Bronchial responsiveness was assessed with a histamine challenge test. The threshold value was defined as the concentration of histamine that caused a decrease in FEV1 of 10% of more (PC10). After a 3-yr interval, a change of the threshold value with two or more doubling concentrations occurred in 21% of the subjects. This proportion increased to 43% if the time between two measurements increased to 18 yr. Of all subjects with multiple observations, 41% were always nonresponders (PC10 > or = 32 mg/ml), 11% were always responders (PC10 < or = 16 mg/ml), and 48% changed responder status. Of the subjects with greater than three observations, 65% changed responder status. Regression analyses, stratified by symptom status, sex, and smoking habit, were used to estimate intraclass correlation coefficients (ICC) as a measure of variability of responsiveness. On average, ICC values were low (0.40), also indicating considerable variability. With adjustment for FEV1, age, area of residence, and eosinophil count, the ICC values decreased slightly. This indicated that with adjustment, the total variability decreased more than the within-subject variability. ICC values did not differ significantly between asymptomatic and symptomatic subjects. Analyses of responsiveness as a binary variable revealed similar results.

The administration by aerosol of the nitric oxide (NO) synthesis inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME) or Ng-monomethyl-L-arginine (L-NMMA), to spontaneously breathing anesthetized guinea pigs resulted in a significant enhancement of lung resistance (RL) after increasing intravenous doses of histamine. The maximal response was increased (p < 0.01) by 126% (L-NAME) and 282% (L-NMMA) compared with the control groups. This effect was inhibited by giving an aerosol of the NO precursor L-arginine (L-Arg) but not by its inactive enantiomer D-arginine (D-Arg). Perfusion through the lumen of guinea pig tracheal tubes in vitro with nitric oxide synthesis inhibitors (120 microM) resulted in a significant increase in basal tone, suggesting a role for NO in the maintenance of basal tone. In addition, the histamine concentration-response curve was significantly shifted upward: the maximal response was increased (p < 0.01) by 335% (L-NAME) and 250% (L-NMMA) compared with the control group. This effect was concentration dependently inhibited by coincubation with L-Arg (120, 200, and 400 microM), but not with D-Arg (200 microM). Furthermore, removal of the epithelium resulted in an upward shift in the histamine concentration-response curve: the maximal response was increased by 185%. However, incubation with L-NAME did not further increase tracheal responsiveness to histamine, but addition of L-Arg (360 microM), when a plateau was reached, relaxed the tissues to control values. Nitric oxide synthesis inhibition did not change the responsiveness of intact tissues in vitro after intraluminal stimulation with leukotriene D4, serotonin, or the cholinergic agonist arecoline.(ABSTRACT TRUNCATED AT 250 WORDS)

Study Objective: In a previous study a higher than expected prevalence of asthma was found in Lake Munmorah, a coastal town near two power stations, compared with another coastal control town. This study aimed to compare atopy, bronchial hyperreactivity, and reported symptoms of asthma in the power station town and a second control area with greater socioeconomic similarity., Design: A cross sectional survey was undertaken., Settings: Lake Munmorah, a coastal town near two power stations, and Dungog, a country town in the Hunter Valley, NSW, Australia., Participants: All children attending kindergarten to year 6 at all schools in the two towns were invited to participate in 1990. The response rates for the questionnaire for reported symptoms and associated demographic data were 92% in Lake Munmorah and 93% in Dungog, with 84% and 90% of children respectively being measured for lung function, atopy, and bronchial reactivity. There were 419 boys and 432 girls aged 5 to 12 years., Measurements and Main Results: Main outcome measures were current wheeze and bronchial hyper-reactivity, defined as a fall in forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF) of 20% or more. Current wheeze was reported in 24.8% of the Lake Munmorah children compared with 14.6% of the Dungog children. Bronchial hyper-reactivity was similar for both groups--25.2% in Lake Munmorah and 22.3% in Dungog. The mean baseline FEV1 was lower in Lake Munmorah than in Dungog (p < 0.001). Dungog children were more likely to have positive skin test to house dust mite (Dungog 27.0%, Lake Munmorah 20.2%, p = 0.028) but there were no other differences in skin test atopy in the two towns. After adjusting for age, gender, any smoker in the house, and positive dust mite skin test, the odds of current wheeze in Lake Munmorah compared with Dungog was 2.16 (95% confidence interval 1.45, 3.15)., Conclusions: Baseline lung function was lower and reported symptoms of asthma were higher in the power station town, but bronchial hyper-reactivity and skin test defined atopy were similar in the two communities. These results are consistent with the previous study and confirm the increased presence of reported symptomatic illness in the town near power stations.

Studies of cotton textile workers have found an association between atopy and drop in FEV1 over a workshift. We studied the response of previously nonexposed volunteers with and without a history of mild atopy to a 5-h exposure to 1 mg/m3 of respirable cotton dust in a model cardroom. All participants were nonsmokers, had no history of asthma, and had normal spirometry. Twenty atopic subjects gave a personal history of mild respiratory allergy to pollen, dusts, or animals that had been confirmed by a physician. Thirty-two nonatopic subjects had no history of allergy. Spirometry and a methacholine challenge test were performed 1 to 2 days prior to exposure. Spirometry was repeated immediately before exposure to cotton dust; spirometry and a methacholine challenge were performed immediately after exposure. Atopic subjects showed a significantly higher mean serum IgE level to Phadiatop, a screening test to common inhalant allergens, than did nonatopic subjects (mean percent binding, 32.1 versus 1.5; p < 0.001). Atopic subjects had a significantly greater mean fall in FEV1 during exposure (8.3% versus 4.9%, p < 0.05). The difference in FEV1 decline between atopic and nonatopic subjects was similar in magnitude to that reported for workshift FEV1 declines between textile workers with and without mild atopy. Atopic subjects had significantly higher baseline methacholine responsiveness than did nonatopic subjects (26% versus 0% reaching a PD20, p < 0.0005). After cotton dust exposure, there was a significant increase in airway reactivity in both groups (68% versus 20% reaching a PD20, p < 0.0005). For all subjects combined baseline responsiveness was significantly related to the change in FEV1 after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

We assessed the relationship between the exposure to dust mite allergens and a bronchial response to exercise in 8-year-old schoolchildren. Dust was collected from the mattresses of 1,291 children and the concentration of mite allergens was estimated by a commercially available ELISA test using monoclonal antibodies (ALK, Copenhagen) against the major allergens of Dermatophagoides pteronyssinus (Der pt) and Dermatophagoides farinae (Der f). A positive bronchial response to exercise (decrease of peak expiratory flow > or = 15% after exercise) occurred in 21 (22.6%) of 101 children sensitized to mite allergens (wheal size > or = 4 mm) and in 51 (4.8%) of 1,070 nonsensitized children. In the highest exposure groups (> 10 micrograms allergen/g dust), 15% of children sensitized to Der f and 20% of children sensitized to Der pt were responsive to exercise. Corresponding figures for the lowest exposure groups (< 0.4 micrograms allergen/g dust) were 11 and 28%, respectively. This negative finding may indicate that measurement of allergen concentration in mattresses does not reflect true exposure or alternatively that at the age of 8 years high exposure to dust mite allergens does not affect bronchial response to exercise in sensitized children.

The association of age, gender, number of eosinophils, area of residence, cigarette smoking, respiratory symptom prevalence, and FEV1 with the level of bronchial responsiveness was studied in a random sample of 2,216 subjects aged 15 to 72 yr. Subjects participated in the Dutch longitudinal study on chronic obstructive pulmonary disease. In 18 yr of follow-up, 5,012 observations were collected. Interviewers used a standardized questionnaire to assess the presence of respiratory symptoms. Bronchial responsiveness was measured by a histamine challenge test. Because multiple measurements within a subject are correlated, multivariate regression methods for correlated outcome were used. A greater number of eosinophils, skin test positivity, and living in a rural area (Vlagtwedde) were associated with increased responsiveness, independently of the level of FEV1 and the presence of respiratory symptoms. Older age was associated with increased responsiveness, and this was even more so in subjects with symptoms. Cigarette smokers were more responsive than nonsmokers, but this association was not significant if the level of FEV1 was taken into account. Hyperresponsiveness was more likely to be present if the amount of cigarettes smoked per day was greater. The level of responsiveness did not differ significantly between males and females. For the same degree of obstruction, however, expressed as the FEV1/VC ratio, males tended to be less responsive than females. The analyses were repeated using the dose-response slope as a continuous measure of responsiveness and by applying a method to adjust for censoring the responsiveness data. These analyses yielded identical results.

We examined the effect of activated alveolar macrophages (AM) on airway responsiveness to muscarinic stimulation in 33 adult Sprague-Dawley rats. An isolated-perfused lung preparation was used to ensure precise and uniform delivery of cells into peripheral airways. The bronchoconstrictor response to acetylcholine (ACh) delivered into the pulmonary arterial circulation was augmented in 8 rats after infusion of 3 x 10(6) AM activated with 10(-6) M f-met-leu-phe and 5 micrograms/ml of cytochalasin B. Lung resistance (RL) caused by 10(-6) mol ACh increased 2.5-fold from 0.10 +/- 0.004 cm H2O/ml/s before infusion of activated AM to 0.35 +/- 0.05 cm H2O/ml/s after infusion of activated AM (N = 8; p < 0.05); the response to ACh was not augmented after infusion of nonactivated AM (N = 7) or vehicle control (N = 6). Baseline RL before ACh was similar in all three groups (p NS). Perfusion with activated AM also significantly increased the wet/dry (W/D) lung weight ratios (7.1 +/- 0.5) compared with nonactivated AM (5.2 +/- 0.1) or vehicle control (5.5 +/- 0.3) (p < 0.05 versus either nonactivated AM or vehicle control). A63162, a 5-lipoxygenase inhibitor, but not indomethacin, a cyclooxygenase inhibitor, completely inhibited augmentation of bronchoconstrictor responses to ACh caused by activated AM and also completely attenuated the increase in W/D lung weight ratios. A highly significant (p < 0.01) correlation (R = 0.76) between W/D lung weight ratios and RL was observed after 10(-6) mol ACh (the greatest dose of ACh administered). Baseline RL was equivalent for all groups before and after infusion of cells or vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-nine asthmatic patients hypersensitive to Dermatophagoides pteronyssinus were treated for a total of 4 yr with injections of complexes made of allergen and autologous specific antibodies. The results obtained throughout the first 2 yr of a double-blind placebo-controlled trial have been published (1) and we now report the results of such therapy during an additional 2 yr. Three groups of patients had been defined: Groups A and B were comprised of patients treated with either "higher" doses of complexes (Group A) or "lower" doses (Group B), whereas Group C received the placebo preparation. Four injections of complexes were performed during the third yr and none during the fourth yr. The clinical benefit resulting from such injections was maintained until the end of the study, whereas medication intake, especially systemic or high doses of inhaled corticosteroids, was much reduced. Skin reactivity to allergen was significantly decreased in both treated groups. Bronchial provocation tests were carried out at 1-yr intervals with either allergen or acetylcholine (ACh). Reactivity to allergen inhalation was significantly decreased at each time point. Reactivity to ACh was significantly decreased at the end of Years 3 and 4. Fifty percent of treated patients who underwent bronchial challenges lost their bronchial reactivity to the highest concentrations of both allergen and ACh. A significant improvement in the basal lung function was observed in both treated groups. The long-term effects of immunotherapy with allergen-antibody complexes in allergic asthma patients thus include reduction in nonspecific bronchial reactivity.

A significant increase in airway responsiveness to histamine was observed in vitro and in vivo 4 days after intratracheal inoculation of parainfluenza Type 3 (PI-3) virus to guinea pigs. Light microscopic and ultrastructural examination of the central airways of animals inoculated with virus revealed stratification of the epithelial lining, with pronounced loss of cilia and granule-depleted goblet cells. In the peripheral airways, typical lesions of patchy alveolitis and bronchiolitis were found. The alveolar epithelium often lacked Type I alveolar cells and was lined merely by cells containing osmiophilic lamellar bodies typical of Type II alveolar cells. PI-3 virus inoculation resulted in a reduction in the number of airway mucosal mast cells, particularly in the bronchioles, and in a change of density of the granules of mast cells. Further, a significant rise (100%) in histamine concentration was observed in lung lavage fluid after virus inoculation. The prostaglandin E2 (PGE2) content in the lavage fluid was not changed. After stimulation with histamine, the tracheae of animals inoculated with control solution or PI-3 virus produced similar amounts of PGE2. These data indicate that PI-3 virus activates airway mast cells and increases the histamine content in the respiratory tract. Neither the virus-induced lung damage nor the increased levels of histamine in the airways influence the release of the epithelially derived relaxing factor PGE2. It is suggested that mast cell-derived products, in particular histamine, are involved in virus-induced airway hyperresponsiveness.

We wanted to test the hypothesis that childhood airway hyperresponsiveness, even in the absence of respiratory symptoms, is a risk factor for respiratory disease in adulthood. In a childhood survey of 1963, three groups of 20 children aged 8-11 yrs, were selected from a population sample: 1) a group with recurrent respiratory symptoms (symptomatic group); 2) a group with no symptoms but a positive family history of atopy; and 3) a control group. All children completed assessment of symptoms, atopy, lung function, and airway hyperresponsiveness. At the adulthood survey 27 yrs later, 85% of the original sample were reinvestigated. Only 10 out of 19 subjects (53%) of the original symptomatic group still had symptoms. The significant difference of forced expiratory volume in one second (FEV1) % predicted in childhood between the symptomatic and the control group had disappeared. The prevalence of airway hyperresponsiveness had decreased in all groups. In asymptomatic hyperresponders it had normalized at adult age. The asymptomatic hyperresponders in childhood had lower levels of lung function, both in childhood and in adulthood. In univariate and multivariate analyses, respiratory symptoms at adult age were related to childhood atopy. Results suggest that childhood atopy is a risk factor for respiratory symptoms in young adulthood, but that mild childhood airway hyperresponsiveness is not.

Bronchial responsiveness to histamine or methacholine provides a useful objective measure for epidemiological studies of airways disease, but most people in a community population do not have a 20% fall in forced expiratory volume in one second (FEV1) with the highest dose administered. Histamine challenge data were analysed to compare the repeatability. Normality and separation of symptom groups of the early dose-response slope with provocative dose producing a 20% fall in FEV1 (PD20). Tests were continued until a 20% fall in FEV1 occurred, or 4 mumol had been given. Data were available for 510 randomly selected subjects, and for an additional 283 with wheeze. A repeat test was obtained in 104 individuals. PD20 was estimated by curve fitting, with extrapolation to 8 mumol. Least-squares slope of percentage decline in FEV1 on histamine dose was calculated, using all the measured points and two-point slope as the fall from the post-saline measurement to the maximum cumulative dose divided by the maximum dose. Log transformation of PD20 and shifted reciprocal transformations of slope produced constant variance. Over all subjects the three measures had similar repeatability; in subjects with PD20 > 8 mumol the intraclass correlation for two-point slope was only 0.26, but was 0.66 for least-squares slope. Neither measure of slope was normally distributed, but the distribution of log(PD20) was consistent with a censored normal distribution. In conclusion, least-squares slope is preferable to two-point slope for epidemiological studies.(ABSTRACT TRUNCATED AT 250 WORDS)

We wanted to examine the predictive nature, over one year, of bronchial hyperresponsiveness (BHR) and recent wheeze (in the previous 12 months), which are the measurements frequently used to classify asthma for epidemiology. A prospective cohort study of 236 children, aged 8-11 yrs, was undertaken, with an initial baseline study, followed by four studies at three monthly intervals over one year. At each study, we measured bronchial responsiveness to histamine by the rapid method, respiratory symptoms by parent questionnaire, and atopy by skin prick tests to common allergens. Airflometer readings, which are closely related to FEV1, were self-recorded. Baseline data were used to classify children into the four categories of "current asthma" (BHR and wheeze), "wheeze only", "BHR only", or "normal". During the year following baseline study, the group initially classified as "wheeze only" had normal Airflometer variability, and 59% had wheeze, and 33% had BHR, which tended to be mild. In the group initially classified as "BHR only", 52% had wheeze with a peak in winter, and 62% had BHR during the following year. This group had more severe bronchial responsiveness and Airflometer variability than the normal and wheeze only groups. The group initially classified as current asthma had a more severe condition, with continued BHR (100%), and wheeze (93%), increased Airflometer variability and more atopy. Thus, the natural history of bronchial responsiveness, respiratory symptoms and allergic history in this group was different from the other three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to investigate whether recent and previous subclinical viral respiratory infection can explain the presence of increased bronchial responsiveness to histamine. We studied a randomly selected population of 495 children and adolescents, aged 7-16 years, from Copenhagen. If the subjects had had symptoms of respiratory infection recently, the examination was postponed for at least 6 weeks. Bronchial hyperresponsiveness (BHR) to inhaled histamine was found in 79 (16%) of the subjects, of whom 28 had asthma. Forty-eight subjects (10%) had increased levels of serum IgM antibodies against either parainfluenza, influenza, adenovirus, or respiratory syncytial virus (RSV), reflecting a recently acquired infection. No association between BHR and antibodies against respiratory viruses was found, as 7 (8.9%) of the 79 subjects with BHR and 41 (9.9%) of the 416 subjects without BHR had viral antibodies. Furthermore, no association between degree of bronchial responsiveness and viral antibodies was found. Moreover, 251 individuals (51%) had signs of earlier RSV infection, i.e. IgG antibodies against RSV. No relationship was found between age of the subjects and the presence of antibodies against either respiratory viruses in general or IgG-RSV. No relationship was found between the presence of antibodies against RSV and BHR; furthermore, evidence of earlier RSV infection was unrelated to the level of lung function and degree of bronchial responsiveness. We conclude that increased bronchial responsiveness in asymptomatic, unselected schoolchildren and adolescents is not likely to be caused by recent or previous viral respiratory infections.

A cross-sectional study was carried out on a random sample of 2,216 schoolchildren 9 to 14 yr of age to determine the prevalence of exercise-induced airway narrowing (EIAN) in a Mediterranean town (Mataró). A complementary case-control study measured the association between EIAN and respiratory symptoms. A free-running test was performed during school time. Peak expiratory flow rate (PEFR) was measured at rest and at 2, 5, 10, and 15 min after exercise. A total of 136 of 2,056 satisfactory runs showed a decrease of PEFR equal to or higher than 15% at each of these times after exercise. Five more children developed wheezing during running and were considered to have EIAN. Prevalence of EIAN was 6.9% (95% CI = 5.9 to 7.9). Prevalence decreased progressively with age. No sex difference was found. In the case-control study a questionnaire of respiratory symptoms was applied to the mothers of hyperresponsive children, as well as to two matched control subjects for each case. Questionnaire analysis showed a strong association between EIAN and respiratory symptoms or rhinitis. Association with bronchitis before 2 yr of age and parental asthma was less but significant.

Methacholine challenge testing is the most commonly used method for detecting and quantifying nonspecific bronchial hyperresponsiveness and has been used primarily in the clinical investigation of occupational asthma. This chapter reviews the rationale, methodology, and interpretation of this test which are relevant to conducting methacholine challenge testing outside the clinic ("in the field"). It also reviews the issues surrounding the methodology of methacholine challenge testing in general and, in particular, its use in epidemiologic studies.

Increased airway hyperresponsiveness is thought to be one of the phenomena underlying nocturnal airway obstruction in asthma. To investigate the mechanisms that influence and modulate this phenomenon, we compared circadian variations in airway responsiveness with AMP and propranolol with the circadian variation in airway responsiveness to methacholine. Inhalation provocation tests were performed at 16.00 and 04.00 h in 16 nonsmoking atopic asthmatic subjects (18 to 42 yr of age), prospectively assigned to Group 1 (mean circadian peak expiratory flow rate [PEFR] variation > or = 15%) and Group 2 (< 15%). The circadian change in airway responsiveness to AMP, in contrast to methacholine, was significantly related to the circadian PEFR-variation of the 16 subjects (r = 0.81, p < 0.001). In Group 1 (n = 7) geometric mean PC20 AMP decreased more than PC20 methacholine during the night (2.3 and 0.9 doubling concentrations respectively, p < 0.05), whereas no difference in baseline FEV1 was found at the same time points during the different study days. Geometric mean PC20 propranolol did not change during the night. Daytime PC20 propranolol and PC20 AMP, in contrast to PC20 methacholine, were significantly lower in Group 1 as compared with Group 2. Together, the results show a higher susceptibility to stimulation of "indirect" airway responsiveness in the subjects with increased circadian PEFR amplitude. This suggests that mast cell activation rather than primary changes in smooth muscle cell contraction may play a role in the development of nocturnal airway obstruction.

Background: There is a need for a new respiratory symptoms questionnaire for use in epidemiological research in asthma., Method: A questionnaire was designed following a pilot study in 78 subjects. It contains nine questions on symptoms such as wheeze and difficulty with breathing in defined circumstances such as exercise and sleep. It was completed by 211 adults and validated by comparison with a self reported history of asthma and with bronchial hyperresponsiveness to histamine. Its short term reproducibility was measured by three repeat administrations over two weeks., Results: Subjects with asthma (n = 33), particularly those having had an asthma attack in the last year (n = 23), were more likely to report any symptom and to report a greater number of symptoms than those without asthma. The same relationship was found for bronchial hyperresponsiveness and symptoms. Either two or more, or three or more, symptoms appeared to be good indices of self reported asthma and bronchial hyperresponsiveness, or both, with a high sensitivity (65-91%) and specificity (85-96%). Reproducibility was good, with few subjects changing the number of symptoms reported by more than one symptom and none by more than four symptoms. The results compared favourably with those from questions on phlegm production from the MRC questionnaire and were better than those reported for the MRC wheeze questions., Conclusions: The questionnaire will be useful for epidemiological research on asthma and could form part of a new standardised questionnaire with wide applications.

Chronic ovalbumin challenge of sensitized guinea pigs induces bronchoalveolar lavage (BAL) eosinophilia, neutrophilia, and tracheal hyperreactivity. In the present study, the influence of monoclonal antibody to murine interleukin-5 (anti-IL-5) on these phenomena is examined. In ovalbumin-sensitized guinea pigs treated with isotype-matched control antibody and challenged daily with ovalbumin for 8 days, the number of BAL eosinophils and neutrophils is increased significantly six- and fivefold, respectively, compared with saline-challenged animals. The maximal contractions of tracheal rings to histamine and arecoline in ovalbumin-challenged animals are enhanced significantly to 155% compared with saline-challenged animals. In sensitized guinea pigs treated with anti-IL-5, the BAL eosinophil number is markedly inhibited compared with control antibody treatment in both saline- and ovalbumin-challenged animals. In contrast, the number of neutrophils is not affected by anti-IL-5 treatment. In guinea pigs treated with anti-IL-5, the development of hyperreactivity to histamine and arecoline after ovalbumin challenge is completely inhibited. The contractions to histamine and arecoline of tracheal rings isolated from guinea pigs treated with recombinant murine IL-5 for 3 or 7 days are enhanced significantly to approximately 140% compared with controls. Treatment with IL-5 for 7 days tends to increase the number of eosinophils in BAL fluid. It can be concluded that IL-5 is involved in airway eosinophilia and in the development of hyperreactivity in this animal model, but other cytokines may contribute. Development of IL-5 synthesis inhibitors and/or receptor antagonists could provide another therapeutic class of anti-asthma drugs.