Prevalence and predictors of bronchial hyperresponsiveness in children aged 7-16 years

To study the prevalence and possible predictors of bronchial responsiveness we examined a cross-section of 527 children aged 7-16 years from Copenhagen. The method used included an interview with the child and the parents, skin prick test with common allergens and se-IgE. Bronchial responsiveness was measured by a histamine inhalation test. We found that 79 (16%) of the children had bronchial hyperresponsiveness (BH), defined as a 20% fall in FEV1 with a provoking concentration of histamine (PC20) at 8 mg/ml or less. Atopic symptoms defined as asthma, rhinitis or eczema were significantly (P less than 0.001) correlated to BH both in prevalence and degree of BH. None of the children with urticaria had BH. The degree of bronchial responsiveness was also significantly influenced (P less than 0.001) by family disposition to atopy, whereas we found no correlation between BH and "passive" smoking, specific skin test in unselected children, or elevation of IgE in children without atopic symptoms. We conclude that BH is severest in children with asthma, independent of elevated IgE or positive skin prick test. Children with rhinitis, dermatitis, or asymptomatic BH have the same degree of BH; this differed from that in children with asthma.     

The relationship between atopy and non-specific bronchial responsiveness

Atopy is often regarded as a risk factor for the development of asthma, particularly childhood asthma and occupational asthma. This could reflect an association with non-specific bronchial responsiveness (NSBR), though atopy could influence asthma independently. We have evaluated the possible relationship between atopy and NSBR (PD20FEV1 to methacholine) in the siblings of 59 probands with atopic asthma. Thirty-four (58%) were atopic (greater than or equal to 1 prick test with weal diameter greater than or equal to that of a 0.1% histamine control) and 28 (47%) showed NSBR. Atopy and NSBR occurred together more frequently than would be expected by chance (P less than 0.05); both variables being observed in 20 subjects, neither in 17, and only one in 22. A significant association was also noted when atopy was defined by a serum total IgE greater than 150 IU (or greater than 50 IU), but when atopy was defined by other commonly used criteria (greater than or equal to 2 prick tests with weal diameter greater than or equal to histamine control; or weal diameter 2 mm or more greater than a saline control), no significant association was demonstrated. Furthermore, linear logistic regression and multiple regression analyses showed that both the presence and the degree of NSBR were influenced much more by the baseline level of FEV1 than by atopic status. At best, atopy accounted for 10% of the variance of the PD20 measurements. We conclude that atopy is associated with NSBR but not strongly; that the relationship may be readily obscured according to the defining criteria used for atopy; and that atopy should not be used as a marker for NSBR.     

Bronchial responsiveness to inhaled histamine and exercise.

Bronchial responsiveness to inhaled histamine and exercise was measured in 19 asthmatics. Histamine aerosol was inhaled to determine the provocative concentration producing a 20% fall in forced expired volume in one second (FEV1) (PC20). Exercise was performed on a treadmill and a cycle ergometer; following each procedure the percent fall in the FEV1 (delta FEV1) and the exercise lability (percent rise in FEV1 plus percent fall in FEV1) were calculated. Delta FEV1 and exercise lability after both forms of exercise were similar. PC20 correlated with delta FEV1 and exercise lability in both forms of exercise; however, the correlation with exercise lability was better. PC20 was more sensitive in demonstrating bronchial hyperresponsiveness. The close correlation between the level of bronchial responsiveness to histamine and exercise supports the view that release of endogenous chemical mediators is an important determinant of exercise-induced asthma. The treadmill exercise and cycle ergometry protocols were equally effective in producing exercise-induced asthma.     

Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms

Functional abnormalities of the extrathoracic airway (EA) may produce symptoms mimicking bronchial asthma. We assessed the bronchial (B) and EA responsiveness to inhaled histamine in 40 patients with asthmatic symptoms and in nine asymptomatic controls. FEV1 and maximal mid-inspiratory flow (MIF50) were used as index of bronchial and EA narrowing. Hyperresponsiveness of the intra-(BHR) or extra-(EA-HR) thoracic airway was diagnosed when the provocative concentrations of histamine (PC20FEV1 or PC25MIF50) were less than 8 mg/ml. Fiberoptic laryngoscopy was performed in nine patients and three controls. The glottal region was measured at mid-volume of maximal inspiration (AgMI) and expiration (AgME) before and after histamine. Predominant EA-HR was found in 13 patients, predominant BHR in 12, equivalent BHR and EA-HR in another 12; no significant airway narrowing was observed in three patients and in the nine controls. EA-HR was significantly associated with female sex, sinusitis, post-nasal drip, dysphonia; BHR with atopy, wheezing and lower MEF50. The percent change in AgMI after histamine was closely related to the PC25MIF50 (r = 0.87, P less than 0.001), that of AgME to the PC20FEV1 (r = 0.78, P less than 0.01). These findings suggest that the assessment of EA responsiveness may be useful in the evaluation of asthmatic symptoms, especially in patients with no BHR.     

Atopy and bronchial responsiveness in random population sample of 527 children and adolescents.

The relationship between bronchial responsiveness, lung function, and results of skin prick testing was studied in 527 children and adolescents from Copenhagen. All participants completed a questionnaire concerning allergic symptoms (asthma, rhinitis, atopic dermatitis, and urticaria). Furthermore, skin prick test reactivity to nine common aeroallergens, lung function, serum IgE and bronchial responsiveness to histamine and exercise were measured. A total of 53 subjects were atopic, (skin prick 3+), 105 subjects had moderate skin reactivity (1-2+), and 366 subjects had no signs of atopic disease (prick test negative); 58% of the subjects with skin test reactivity (1-3+) were asymptomatic. Increasing degree of atopy was correlated significantly with symptoms such as asthma, rhinitis, dermatitis, and urticaria (P less than .001); increasing level of IgE (P less than .001); month of birth (P = .001); and family history of allergic diseases (P less than .05). The most important markers for the degree of bronchial responsiveness to inhaled histamine were the presence of respiratory symptoms (P less than .001), the degree of atopy (P = .001), a history of asthma in at least two first degree relatives (P less than .01), and the skin reactivity to house dust mites (P = .001), horse epithelium (P = .01), Alternaria iridis, and dog epithelium (P less than .05). In contrast, the degree of bronchial responsiveness to exercise was significantly correlated with asthma (P less than .001), the level of IgE (P less than .05), month of birth (P less than .001), and birth weight (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Atopy and bronchial hyperresponsiveness: exclusion of linkage to markers on chromosomes 11q and 6p

Previous studies have reported a familial predisposition for the development of atopy, bronchial hyperresponsiveness and clinical asthma, and therefore have suggested the presence of a heritable component to these disorders. The specific contributions of genetic and environmental factors in the pathogenesis of allergic disease and asthma have not been determined although Cookson et al. [1] have postulated linkage between atopy and chromosome 11q. We have studied 20 families (two and three generations) ascertained through a proband identified as having asthma (90% were also allergic) during the period of time between 1962 and 1970. Of those who were originally skin test positive, 82% remained positive. All probands whose pulmonary function allowed retesting (FEV1 > 1.2 l) remained hyperresponsive to histamine. The children of these probands are now in the same age range as their parents when they were originally evaluated; 66% are atopic using criteria described by Cookson et al. (one or more positive skin tests > or = 2 mm, an elevated total serum IgE or a positive specific IgE) and 22% demonstrate bronchial hyperresponsiveness (PC20 FEV1) to histamine. Using the highly polymorphic marker INT2 (which maps 2 cM from p lambda MS.5 l on chromosome 11q) and atopy, we obtained a lod score of -2.00 at a recombination fraction of 0.12. In addition, because many studies have suggested an association between atopy and certain HLA antigens, we investigated the possibility of linkage between atopy and bronchial hyperresponsiveness and D6S105, a polymorphic marker on chromosome 6p, located 7 cM from HLA-DR. For this marker and atopy, we observed a lod score of -2.00 with a recombination fraction of 0.07.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of bronchial responsiveness to histamine in asthma, allergic rhinitis and allergic sensitization at the age of 7 years

BACKGROUND: Bronchial responsiveness (BR) to histamine or methacholin is a common finding in adult non-asthmatic patients with allergic rhinitis. OBJECTIVE: We tested whether BR is also present in children with a comparatively short history of allergic rhinitis in a paediatric cohort. METHODS: We performed pulmonary function tests and histamine challenges in a total of 654 children (age 7 years, participants of the German Multicenter Allergy Study) and compared PC20 FEV1 values in children with asthma, allergic rhinitis, asymptomatic allergic sensitization and non-atopic controls. RESULTS: Most pronounced BR to histamine was observed in allergic asthmatics (n = 28), irrespective of the presence or absence of allergic rhinitis. Furthermore, PC(20)FEV(1) values in non-asthmatic children with allergic rhinitis (n = 24) were not significantly different from those seen in asymptomatic atopic (n = 54) or non-atopic controls (n = 92). CONCLUSIONS: In contrast to adult study populations, 7-year-old non-asthmatic children with allergic rhinitis do not show a higher degree of BR than asymptomatic atopic or non-atopic controls. Therefore, secondary preventive measures in non-asthmatic children with allergic rhinitis (such as regular local anti-inflammatory therapy or specific immunotherapy) should be studied and applied more intensely to prevent bronchial hyper-responsiveness (BHR) and asthma in this high-risk group.     

Bronchial responsiveness to exercise in a random sample of 494 children and adolescents from Copenhagen

To investigate the bronchial response to exercise, we studied a random sample of 494 children and adolescents, aged 7-16 years, from Copenhagen. Exercise challenge consisted of steady running on a 10% sloping treadmill for 6 min in a climate chamber. Furthermore, in 464 subjects a histamine challenge test was also performed. Of the 494 subjects studied, 81 (16%) had at least 10% and 30 (6%) at least 15% reduction in FEV1 within 15 min after exercise. Twenty-nine (6%) subjects had bronchial hyperresponsiveness to both histamine and exercise, 48 (10%) subjects had bronchial hyperresponsiveness to exercise, but histamine responsiveness within the normal range, whereas 340 (73%) subjects had neither bronchial hyperresponsiveness to exercise nor inhaled histamine. With regard to the presence of asthma defined as substantial exercise induced bronchoconstriction (delta-FEV1 greater than or equal to 10%), exercise testing may not be appropriate for identifying clinical asthma in a random sample, because the highest predictive value of a positive test was 25%. On the other hand, a history of clinical asthma was frequently associated with increased bronchial responsiveness to exercise (77%). In conclusion, 16% of a random sample of children and adolescents had abnormal bronchial responsiveness to exercise (delta FEV1 greater than or equal to 10%), 6% of the subjects had a delta FEV1 greater than or equal to 15%. Furthermore, because of a low predictive value of a positive test, the exercise challenge test has only a supplementary role in the detection of clinical asthma in population samples.     

Bronchial hyperresponsiveness in atopic dermatitis

We investigated the prevalence of bronchial asthma, immediate skin reactivity and bronchial hyperresponsiveness in 40 patients with atopic dermatitis (AD). Eight patients reported to have asthma while 29 were found responders to methacholine test (PC20 Mch less than 64 mg/ml) and 21 were skin reactors. The prevalence of skin positive reactions did not differ in responder and non-responder (PC20 Mch greater than 64 mg/ml) groups. Males were more likely both to have bronchial asthma and be responders to methacholine test than females. Moreover, responders had an earlier age of onset of AD than the non-responders. We suggest that bronchial responsiveness should be evaluated in children with AD.     

Bronchoconstriction due to isocapnic cold air inhalation minimally influences bronchial hyperresponsiveness to methacholine in asthmatic subjects

The aim of this study was to investigate if bronchial hyperresponsiveness to methacholine could be influenced by a previous bronchoconstriction due to isocapnic inhalation of cold air. Twelve adult asthmatic subjects in a clinical steady state were seen on four different days in a randomized way according to three different sequences. After assessment of spirometry, bronchial responsiveness to inhaled methacholine was determined on each occasion by the provocative concentration causing a fall of 20% in FEV1 (PC20). On two occasions, the methacholine test was preceded by the inhalation of dry cold air which caused significant (greater than 20% change in FEV1) bronchoconstriction. The methacholine test was performed after functional recovery. There was a significant (t = 2.53; p less than 0.05) but minimal (mean changes of 0.65 single two-fold concentration difference) reduction in PC20 after cold air inhalation. It is concluded that cold air-induced bronchoconstriction causes significant but minimal changes in bronchial responsiveness to methacholine in asthmatic subjects.     

Relationship between nasal and bronchial responsiveness in perennial allergic rhinitic patients with asthma

BACKGROUND: The nasal and bronchial mucosa present similarities and most patients with asthma also have rhinitis, suggesting the concept of 'one airway one disease'. Although many studies may suggest the relationship between nasal and bronchial responsiveness in patients with allergic rhinitis and asthma, few studies have been published which address this question directly. The aim of this study is to investigate whether the relationship between nonspecific nasal and bronchial responsiveness exists in perennial allergic rhinitic patients with asthma. METHODS: Fifty-one perennial allergic rhinitic patients with the definitive or suspected asthma underwent methacholine bronchial provocation tests and nasal histamine challenge tests. A slope of the absolute changes in nasal symptoms score/log concentrations of histamine was calculated by linear regression analysis. A ratio of the final absolute change in nasal symptoms score to the sum of all the doses of histamine given to the subject was also calculated. The degree of bronchial responsiveness to methacholine was categorized as positive bronchial hyperresponsiveness (BHR) if PC(20) (provocative concentration of methacholine resulting in 20% fall in FEV(1)) was <4 mg/ml, borderline BHR if PC(20) was >or=4 but 16 mg/ml. Another index of bronchial responsiveness (BRindex) was calculated as the log [(% decline in FEV(1)/log final methacholine concentration as mg/dl) + 10]. RESULTS: The geometric means of the slope (4.47 vs. 2.95, p < 0.05) and the ratio (1.68 vs. 0.54, p < 0.01) were higher in patients with positive BHR (n = 23) than in patients with negative BHR (n = 19), respectively. The geometric means of the slope (3.50) and the ratio (1.13) in patients with borderline BHR (n = 9) were between the two groups, respectively. In all patients, the log-slope (r = 0.48, p < 0.001) and the log-ratio (r = 0.51, p < 0.001) were correlated well with the BRindex, respectively. Even in allergic rhinitic patients with definitive asthma, the log-slope was correlated with the BRindex (r = 0.39, p < 0.05) or log-PC(20) (r = -0.36, p < 0.05). CONCLUSIONS: The nonspecific nasal responsiveness may be related to the nonspecific bronchial responsiveness in patients with allergic rhinitis and asthma, which may support the viewpoint that allergic rhinitis and asthma represent a continuum of inflammation involving one common airway.     

A comparison of the effects of nedocromil sodium and beclomethasone dipropionate on pulmonary function, symptoms, and bronchial responsiveness in patients with asthma

The efficacy of nedocromil sodium (NED) (4 mg twice daily) and beclomethasone dipropionate (BDP) (200 micrograms twice daily) in controlling the symptoms of asthma, the pulmonary function, and bronchial responsiveness to histamine was assessed in a double-blind, double-dummy, crossover study of 39 adult patients with chronic asthma. The patients, most of whom were assessed to be affected to a moderate degree, were insufficiently controlled in their current regimen of inhaled and/or oral bronchodilators. A 2-week baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups demonstrated improvements from baseline in clinical assessment of lung function performed after the first 6 weeks of treatment. No significant differences were observed when the effects of the treatments were compared on FEV1, FVC, and peak expiratory flow. Bronchial reactivity to histamine, measured as the amount of histamine causing a 20% fall in FEV1 (PC20), decreased significantly (p less than 0.05) after 6 weeks of treatment with BDP compared to the effect of NED treatment. Asthma severity, symptom score, and inhaled bronchodilator use demonstrated significantly better results with BDP. After crossover of treatment, the group transferring from NED to BDP continued to improve, whereas the group crossing from BDP to NED tended to demonstrate a major deterioration during the first 3 weeks, after which a stabilization or an increase in FEV1, FVC, and ln PC20 appeared to occur. It is concluded that NED for inhalation is a potent new drug for treatment of both atopic and nonatopic subjects with asthma. With the number of patients and dosages used, the effect on the pulmonary function was not significantly different from that of BDP after the initial 6 weeks of treatment, but BDP had a better effect on asthma severity, overall opinions, symptom score, bronchodilator use, ln PC20, and morning peak expiratory flow.     

Long-term prognosis of asthmatic patients treated with low-dose beclomethasone dipropionate]

To clarify the prognosis of asthmatics treated with low-dose of inhaled beclomethasone dipropionate (BDP), we retrospectively assessed 43 patients treated with initial dose of 200 or 400 micrograms/day for 5 years, and obtained the following results. 1) 15 patients achieved step-down therapy (group A), 17 patients maintained initial dose of BDP (group B), and 11 patients required step-up therapy of BDP or daily use of oral prednisolone (group C). 2) There was no significant difference in age, sex, duration of disease, severity of disease, peripheral eosinophil counts, %FEV1 and histamine PC20 before BDP treatment among three groups. The percentage of atopic asthmatics was significantly higher in group C than in group A. 3) There was no significant difference in symptom and histamine PC20 between after 1 year state and after 5 years state in three groups. 4) After 1 year from the start of BDP treatment, only 18% patients got symptom free and neither patients exceeded 20,000 micrograms/ml of histamine PC20 in group C. Long-term treatment of low-dose BDP inhalation was effective on mild/moderate asthmatics. Patients requiring step-up therapy had not got sufficient improvement in bronchial hyperresponsiveness after one-year treatment.     

Bronchial hyperreactivity after treatment with sodium cromoglycate in atopic asthmatic patients not exposed to relevant allergens

The bronchial hyperreactivity, measured as the responsiveness to histamine, was studied in 14 atopic patients before, during, and after 4 wk of treatment with sodium cromoglycate (SCG) and placebo in a double-blind, randomized, crossover study. The patients were not exposed to relevant allergens during the study. The variations in provocation concentrations corresponding to 20% decrease in FEV1 (PC20) were small during both placebo and active drug treatment. After SCG treatment, PC20 increased (less responsiveness) in nine of the 14 patients, especially in those with low PC20 values. The difference between placebo and active drug treatment was not statistically significant. Although SCG has a mediator-inhibiting effect, this study gave no support for the assumption that inhibition of mediator release leads to a reduction of the bronchial hyperreactivity in atopic asthmatic subjects who are not exposed to relevant allergens.     

Atopy in infancy predicts the severity of bronchial hyperresponsiveness in later childhood

We have prospectively followed 52 children of atopic parents from birth to age 7 years, documenting clinical atopic disease and allergen skin test reactions. We found bronchial hyperresponsiveness (BHR) to histamine in 13 (25%) of the children at 7 years of age with 25 (48%) being atopic on skin testing and 15 (29%) having current wheeze, whereas 30 children (58%) had wheezed at some time during this period. BHR was significantly associated with wheeze and atopy at 5 and 7 years of age, but not during infancy. The six children with moderate to severe BHR (provocative dose causing a 20% fall in FEV1 less than 0.8 mumol) formed a distinct subgroup with significantly more wheeze and atopy both during infancy and at 5 years of age when these children were compared to children with milder degrees of BHR. The group with moderate to severe BHR also differed significantly from the nonhistamine-reactive group, whereas children with milder degrees of BHR were not significantly different. We conclude that subjects most likely to develop the more severe degrees of BHR during later childhood are children who manifest atopy in infancy.     

Sensory neuropeptides are not directly involved in bronchial hyperresponsiveness induced by interleukin-8 in guinea-pigs in vivo

Background Interleukin-8 (IL-8) hus been shown to be a chemotactic factor for netitrophils, T-lymphocytes and eosinophils. Repeated intranasal administration of IL-8 enhances bronchial responsiveness to inhaled histamine in guinea-pigs. Neuropeptides which arc released trotn C-fibre nerve-endings have been postulated to induce bronchial hyperresponsiveness through neurogenic inflammation. Objective This study was conducted to examine whether sensory neuropeptides are involved in the IL-8-induced bronchial hyperresponsiveness. Methods IL-8 at a dose of 5μg/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilaled through tracheal cannula, and lateral pressure at the tracheal cannula (Pao) was measured as an overall index of airway responses lo increasing concentrations of inhaled histamine (25, 50, 100, and 200 μg/mL). A NKI and NK2 dual antagonist FK224(10mg/kg), a selective NK1 antgonist FK888 (10mg/kg) or vehicle was intravenously administered 10min before measurement of bronchial responsiveness. Result The IL-8 treatment significantly enhanced bronchial responsiveness to histamine (ANOVA P < 0.01). FK224 or FK888 did not alter the IL-8-induced bronchial hyperresponsiveness. Conclusion We conclude that repeated intranasal administratioti of IL-8 causes bronchial hyperresponsiveness (BHR) and that neuropeptides such as neurokinin A and substance P do not directly contribute to the development of BHR induced by IL-8.     

Inhibition of allergen-induced asthma by three forms of sodium cromoglycate

The effect of three forms of sodium cromoglycate (SCG), 20 mg, on allergen-induced early asthmatic responses was examined in ten stable asthmatics. Dose response allergen inhalation tests were performed on five occasions at intervals of from 1 to 2 weeks to determine the provocation concentration producing a 20% reduction (PC20 allergen) in FEV₁. Placebo was given before the first and the last tests to determine the reproducibility of responses to allergen over the study period; reduced responsiveness was observed in eight of the ten subjects. Major changes in levels-of specific serum antibodies of the IgE and IgG classes did not serve to explain the changes in bronchial responses although there was a trend which suggested IgG-related desensitization. The observed changes in bronchial responses and antibody levels illustrate the requirement for tests of reproducibility of responses by the use of placebo controls at the beginning and end of a series of allergen inhalation challenges. SCG as (i) a micronized powder with lactose, (ii) micropellets without lactose, or (iii) an aerosol, were inhaled double-blind, in random order, 5 min before the additional three allergen inhalation tests. PC₂₀ allergen was reduced following SCG in seven subjects; the differences were statistically significant for the group. There was no observed difference in efficacy between the different forms of SCG. In this study, the efficacy of SCG could not be related to age, atopic status, the initial level of allergen-specific IgE antibody, baseline FEV₁, level of bronchial responsiveness to inhaled histamine or an effect of SCG on responsiveness to histamine.     

Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy

BACKGROUND: Immunotherapy has been shown to reduce allergen sensitivity to allergens such as cat and dust mite. The aim of this study was to investigate the effect of cat or dust mite immunotherapy on bronchial hyperreactivity and the need for inhaled corticosteroids in children with asthma, cat or dust mite allergy, and hay fever. SUBJECTS: Twenty-nine children, 7 to 16 years old, completed the 3-year study. They were randomly allocated to receive cat/dust mite or placebo and birch/timothy immunotherapy. METHODS: Before immunotherapy was begun and then once each year, bronchial histamine challenges were performed. Bronchial allergen challenge with the perennial allergen was done before and after the 3-year study. Pharmacotherapy was given according to a standardized protocol. RESULTS: PC20 allergen increased significantly in both the active immunotherapy group (P <.001) and in the placebo-pollen group (P <.05). PC20 histamine increased continuously in the active immunotherapy group (P <.05 and P =.002 after 1 and 3 years, respectively) and had also increased after 3 years in the placebo-pollen group (P <.05). The difference between the 2 groups was significant for PC20 allergen (P =.001) but not for PC20 histamine. There was no significant change in the dose of inhaled budesonide needed for symptom control in either of the groups. CONCLUSION: Pollen immunotherapy combined with inhaled corticosteroids results in improvement of both cat/dust mite bronchial sensitivity and hyperresponsiveness to histamine. The combination of cat or dust mite, pollen immunotherapy, and inhaled budesonide enhances this improvement. Cat immunotherapy also induces cat allergen tolerance.     

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.