Allergen PC20 Research Articles

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses

Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240mg every 2weeks for 10weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24weeks after the first dose. QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P=.10) and 16-fold greater than that of placebo (P=.0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.

Bronchial responsiveness to bakery‐derived allergens is strongly dependent on specific skin sensitivity

Quantitative relationships between immunological reactivity, non-specific bronchial responsiveness and bronchial responsiveness to allergens have scarcely been investigated in occupational asthma. We assessed the above relationships in 24 subjects with baker's asthma. The skin endpoint titration to bakery allergens as a measure of immunological reactivity, together with the methacholine PC20 and allergen PC20 during early asthmatic reaction were determined. All patients had positive skin tests to some bakery allergens (wheat and rye flour, soybean flour, fungal enzymes and egg white proteins) and bronchial hyperresponsiveness to methacholine. Specific inhalation challenge (SIC) tests were performed with aqueous allergen extracts of cereal flour (n = 14), soybean (n = 8), baking enzymes (n = 12), and egg white proteins (n = 8) in sensitized workers. A positive asthmatic reaction was observed in 84% of the inhalation challenges. SIC elicited isolated early asthmatic reactions in 62%, dual reactions in 32% and isolated late reactions in 5%. Multiple linear regression analysis showed allergen PC20 as a function of skin sensitivity to allergen and methacholine PC20, yielding the following highly significant regression formula: log-allergen PC20 = 0.18 + 0.99 log(skin sensitivity) + 0.343 log(methacholine PC20) (r = 0.89, P < 0.001). This formula predicted allergen PC20 to within one double concentration in 67%, to within two double concentrations in 85% and within three double concentrations in 97%. The main determinant of bronchial responsiveness to allergen in patients with baker's asthma is the degree of sensitization to occupational allergens as determined by skin reactivity, modulated to a lesser extent by non-specific bronchial hyperresponsiveness.

Effect of combined montelukast and desloratadine on the early asthmatic response to inhaled allergen

The early asthmatic response (EAR) to inhaled allergen results from IgE-mediated release of multiple mast-cell mediators, including leukotrienes and histamine, both of which cause bronchoconstriction. Combination therapy directed at blocking the effects of both mediators might protect against the EAR better than either therapy alone. We sought to evaluate the effect of desloratadine and montelukast, administered alone and in combination, on the EAR to inhaled allergen. Ten adults with mild-to-moderate atopic asthma participated in a randomized, 4-way crossover study design comparing placebo, 5 mg of desloratadine, 10 mg of montelukast, and the combination administered at 26 hours and 2 hours before each allergen challenge conducted at least 7 days apart. The primary end point was the concentration of allergen that resulted in a 20% decrease in FEV1 (PC20). The geometric mean allergen PC20 (mean log +/- SEM) for combination therapy, montelukast, desloratadine, and placebo was 697 U/mL (2.8433 +/- 0.3253), 338 U/mL (2.5295 +/- 0.2979), 123 U/mL (2.0883 +/- 0.2102), and 104 U/mL (2.0166 +/- 0.2553), respectively (n = 9; P < .00001, ANOVA). Montelukast increased the allergen PC20 4.8-fold, and combination therapy increased the allergen PC20 8.9-fold. The effect of the combination was greater than that with montelukast alone (P < .02). Desloratadine treatment was no different than placebo. The early response to inhaled allergen was unchanged after desloratadine therapy and partially inhibited with montelukast therapy. The combination of desloratadine and montelukast provided superior efficacy to either blocker administered alone. Investigations into the possible mechanisms of the enhanced inhibition are necessary.

The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen

The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint. We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation. From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae. In single regressions, allergen PC20 correlated with both methacholine PC20 (r=0.25, P=0.0015) and skin test endpoint (r=0.52, P <0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r=0.61, P <0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations. We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.

From IgE to anti-IgE: where do we stand?

From IgE to anti-IgE: where do we stand?

Effect of Exposure to Low Levels of Ozone on the Response to Inhaled Allergen in Allergic Asthmatic Patients

In a previous study published by our group, six out of nine subjects with mild allergic asthma were shown to have an enhanced response to allergen challenge following a 1-h exposure in an 0.8-m3 exposure chamber (modified from a body plethysmograph) to an average of 120 parts per billion (ppb) ozone at rest. Other studies failed to confirm this effect. In the present study, using a similar design, we reexamined this effect using a larger group of asthmatics and a larger chamber allowing minimal fluctuations in ozone levels during exposures. Prospective, randomized single-blinded crossover study. Pulmonary function laboratory equipped with an exposure chamber. Fifteen subjects had mild allergic asthma; 9 men and 6 women; the mean (SD) age was 32.5 (10) years; FEV1 was 3.4 (0.8) L; baseline methacholine provocation concentration causing a 20% fall in FEV1 was (PC20) 3.28 (4.1) mg/mL. Each participant was exposed, at rest, on 1 day to filtered air and on another day to ozone (mean level=120 ppb) in a larger exposure chamber than the one used in our first study with less variability in ozone level (110 to 130 vs 85 to 175 ppb) using a random, single-blinded design. After each exposure, the subject was challenged with allergen (nine with grass pollen extract and six with ragweed extract) and allergen PC15 was measured. Ozone preexposure did not affect allergen PC15 when compared with clean air preexposure (allergen PC15 dilution 1/114 vs 1/119, respectively). Ozone vs air preexposure resulted in an allergen PC15 that was lower in five subjects, higher in six, and unchanged (within one doubling dose) in four. At this low level with less variability and lower peaks than our previous study, ozone had no significant effect on airway allergen responsiveness.

529 Increased c-fos synthesis in mononuclear cells from patients with corticosteroid resistent asthma

529 Increased c-fos synthesis in mononuclear cells from patients with corticosteroid resistent asthma

Interaction of inhaled beta 2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.

Regular treatment with salbutamol increases airway responsiveness to allergen but not to methacholine and produces tolerance to the bronchoprotective effect of salbutamol. The current study addresses the effect of inhaled corticosteroid on these aspects of regular beta 2 agonist use. A group of 13 atopic asthmatic subjects free from all asthma medications and remote from allergen exposure were studied. We used a double-blind, random-order, crossover study to compare four 1-wk treatment periods with > or = 1 wk washout: placebo, salbutamol, 200 micrograms four times per day, budesonide, 400 micrograms four times per day, and the combination of salbutamol and budesonide. We measured the methacholine PC20 and the methacholine dose shift produced acutely by 200 micrograms salbutamol after 7 d and the allergen PC15 after 8 d treatment. Blinded medications were withheld for 8 to 10 h before measurements. The methacholine PC20 was not affected by regular salbutamol but increased significantly (p < 0.014) after both budesonide-containing regimens. Neither the dose shift nor its significant reduction by regularly used beta 2 agonist were influenced by the inhaled corticosteroid. The four allergen PC15 values were significantly different from each other. Compared with placebo, the allergen PC15 was 0.6 doubling doses lower after salbutamol (p = 0.021) and 1.3 doubling doses higher after budesonide (p < 0.001); the allergen PC15 was reduced by 0.53 doubling doses from this new baseline (p = 0.039) when salbutamol and budesonide were used together.(ABSTRACT TRUNCATED AT 250 WORDS)

Regular inhaled salbutamol and airway responsiveness to allergen

Regular inhaled β2 agonist causes tolerance to the acute protective effect of β2 agonist against bronchoconstriction induced by chemical stimuli such as AMP, histamine, and methacholine. We examined a more clinically relevant stimulus, inhaled allergen, in a double-blind, cross-over, random-order trial in 13 mild atopic asthmatics, who had not used β2 agonist for at least 4 weeks. We compared regular inhaled salbutamol (200 μg four times daily for 2 weeks) with placebo (2 weeks) for effects on bronchodilator response, baseline methacholine, and allergen airway responsiveness, and on the acute protective effect of salbutamol against both stimuli. Baseline forced expiratory volume in 1 s (FEV1), bronchodilator response, and methacholine responsiveness were the same during both treatment periods. After regular salbutamol, the allergen PC20 (provocation concentration producing a 20% FEV1 decrease) fell by 0·91 (SD 0·66) (p=0·0009) doubling doses, and the protective effects of salbutamol on methacholine and allergen were both significantly reduced (p=0·026 and 0·025, respectively). Taking into account the reduced baseline allergen PC20, the post-salbutamol allergen PC20 was almost 2 doubling doses (1 94 [1·43], p<0·01) lower during salbutamol treatment. Thus, 2 weeks of regular inhaled salbutamol increased airway responsiveness to allergen but not to methacholine, and caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both stimuli. These effects of inhaled β2 agonist provide further evidence to support detrimental effects of their regular use.

Bronchial allergen challenge: dose versus concentration.

This study was designed to investigate if two equivalent doses of allergen administered by different dosing regimes--two breaths and 10 breaths of each concentration--would result in the same magnitude of the early and late asthmatic response. Fifteen patients with extrinsic allergic asthma were challenged twice with either two or 10 breaths of twofold increasing allergen concentrations. The challenge was continued until a 20% decrease in FEV1 had been achieved. A non-cumulative PC20FEV1 allergen was derived, and the cumulative dose of allergen given was similarly derived. In order to assess the reproducibility of the challenge, seven patients were challenged twice with two-breath regime. The mean value of allergen PC20 obtained by the two-breath regime was 4.1 fold (95% CI: 2.3-7.1 fold) greater than those obtained by the 10-breath regime (P less than 0.05), whereas the difference was 1.4 fold (95% CI: -3.3-0.5 fold) for the cumulative dose (P greater than 0.05). A statistically significant larger magnitude of the early asthmatic response, as determined by the maximum per cent fall in FEV1, and late asthmatic response determined by the maximum per cent fall in peak expiratory flow domiciliary recorded during the following 24 hr after challenge, was observed in favour of the 10-breath regime compared to the two-breath regime (mean difference 6%, 95% CI: 0.6-11%). The reproducibility of the provocation test was acceptable (+/- 1.8 two-fold concentration difference). These results confirm the 'equivalent dose hypothesis', and demonstrates that dosage rather than concentration appears to determine the early and late asthmatic response after bronchial allergen challenge.

Reproducibility of standardized bronchial allergen provocation test.

Standardized bronchial allergen provocation was performed twice (with an interval of median 14 days (range 14-44)) in 19 extrinsic, well-defined asthmatic patients to study the reproducibility of the bronchial response. Smoking and medications were strictly withheld prior to the provocation. Ten-fold increasing concentrations of allergen solution 0.9 ml were inhaled by tidal volume breathing for 5 min at 10-min intervals. The actual dose given was expressed by the concentration of the solution used. Forced expiratory volume in the first second (FEV1) was used to determine responses, and the provocation continued until an allergen concentration (allergen PC20) was reached which caused at least 20% decrease of the post-saline FEV1. All provocations were followed by a bronchial reaction within clinically acceptable limits. The reproducibility was high, evaluated by the Spearman rank correlation coefficient Rho = 0.90 (P less than 0.01). It is concluded that bronchial provocation with allergens performed as outlined in this study represents a reproducible test which can be applied in routine allergy diagnostics, and in further investigations concerning specific bronchial reactivity.

Determinants of allergen-induced asthma: dose of allergen, circulating IgE antibody concentration, and bronchial responsiveness to inhaled histamine.

The relationships among bronchial responsiveness to allergen, bronchial responsiveness to histamine, and cutaneous sensitivity to allergen were examined in 25 asthmatic subjects. Bronchial responsiveness to allergen was determined by inhalation tests with 2-fold increasing doses of allergen extract, and was expressed as the provocative concentration producing an early asthmatic response with a 20 % decrease in the forced expiratory volume in one second (allergen PC20). Bronchial responsiveness to histamine was determined in a similar way and was expressed as histamine PC20. Cutaneous sensitivity to allergen was determined by duplicate prick skin tests with doubling concentrations of the same allergen extract used for inhalation, and was expressed as the concentration producing a mean wheal diameter of 2 mm. There was a poor correlation between histamine PC20 and cutaneous sensitivity to allergen (r = −0.03, p > 0.1). There was a good correlation between allergen PC20 and histamine PC20 (r = 0.52, p > 0.02...