Francine Deschesnes

Effects of Interleukin-13 Blockade on Allergen-induced Airway Responses in Mild Atopic Asthma

RATIONALE Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity. OBJECTIVES We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma. METHODS Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils. MEASUREMENTS AND MAIN RESULTS The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo. CONCLUSIONS IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

Antisense Therapy against CCR3 and the Common Beta Chain Attenuates Allergen-induced Eosinophilic Responses

RATIONALE The drug product TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides designed to inhibit allergic inflammation by down-regulating human CCR3 and the common beta chain (beta(c)) of IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors. OBJECTIVES This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and beta(c) mRNA and protein levels, and the airway physiologic response after inhaled allergen. METHODS Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1,500 microg TPI ASM8 or placebo by nebulizer, once daily for 4 days. On Day 3, subjects underwent allergen inhalation challenge. Sputum samples were collected before and after allergen. CCR3 and beta(c) protein levels were measured by flow cytometry, mRNA was measured using real-time quantitative polymerase chain reaction, and the FEV1 was measured over 7 hours after challenge. MEASUREMENTS AND MAIN RESULTS Compared with placebo, TPI ASM8 inhibited sputum eosinophil influx by 46% (P = 0.02) and blunted the increase in total cells (63%) after allergen challenge. TPI ASM8 significantly reduced the early asthmatic response (P = 0.04) with a trend for the late asthmatic response (P = 0.08). The allergen-induced (Day 2 to Day 3) levels of beta(c) mRNA and CCR3 mRNA in sputum-derived cells were inhibited by TPI ASM8 (P = 0.039 and P = 0.054, respectively), with no significant effects on the cell surface protein expression of CCR3 and beta(c) (P > 0.05). No serious adverse events were reported. CONCLUSIONS TPI ASM8 attenuates the allergen-induced increase in target gene mRNA and airway responses in subjects with mild asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00264966).

Near-fatal asthma : clinical and physiologic features, perception of bronchoconstriction, and psychologic profile

We studied 19 subjects with asthma (11 men and eight women, aged 20 to 66 years), 6 months to 5 years after a near-fatal (NF) episode of asthma (NF group). Mean duration of asthma was 16.3 +/- 2.4 years. On reevaluation, all subjects were using an inhaled beta 2-agonist and inhaled steroids (mean daily dose of budesonide, 1070 micrograms [N = 5], and beclomethasone, 1079 micrograms [N = 14]). Two subjects were taking prednisone, 10 and 15 mg/day. Subjects were matched for age, sex, atopic status, baseline FEV1, and medication use to a control group (C group) of subjects with asthma who had never experienced an NF asthma episode. All subjects had the following evaluation: (1) questionnaire on the characteristics of their asthma, (2) spirometry, (3) morning and evening measurements of peak expiratory flow rates (PEFR) with daily recordings of asthma symptoms for 4 weeks, and (4) psychometric evaluation with the Minnesota Multiphasic Personality Inventory. Ten subjects of the NF group and 13 of the C group had a methacholine challenge with scoring of dyspnea on a modified Borg scale. Mean percent predicted (+/- SEM), FEV1, FVC, and PEFR were similar for the NF and C groups with respective values of 63.4 (4.4), 61.3 (5.6), 81.1 (4.5), 79.1 (3.8), 61.3 (5.6), and 62.4 (6.1). Geometric mean of the provocative concentration of methacholine causing a 20% drop in FEV1 (milligrams per milliliter) was 0.61 for the NF group (N = 10) and 1.18 for the C group (N = 13).(ABSTRACT TRUNCATED AT 250 WORDS)

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

Background:  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.

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

BackgroundPhosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.Methods25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.ResultsRoflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.ConclusionsThis study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.Trial RegistrationClinicalTrials.gov: NCT01365533

Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model

BACKGROUND Inhaled corticosteroids are the most commonly used antiinflammatory agents for asthma. There is no simple way to compare objectively the relative potency of inhaled corticosteroids. The allergen-induced late asthmatic response (LAR) can be suppressed by a single dose of inhaled corticosteroid. OBJECTIVE This study was undertaken to evaluate LAR as a model for the determination of the relative potency of single doses of inhaled corticosteroids. METHODS We compared doses of 200 and 800 microg of a highly active inhaled corticosteroid (budesonide) with placebo and a marginally active investigational inhaled corticosteroid (D5159). Ten atopic patients with asthma completed a randomized, double-blind, double-dummy, multicenter, four-way, crossover trial. A standardized allergen challenge with the identical dose of allergen was performed 10 minutes after each of four blinded, single-dose treatments: 200 microg of budesonide, 800 microg of budesonide, 8 mg of D5159, and placebo, all administered from Turbuhaler. The LAR was recorded as the maximum percent fall in FEV1 between 4 and 7 hours, and the allergen-induced increase in methacholine airway responsiveness at 24 hours was recorded as the A log PC20 from the day before to the day after allergen challenge. RESULTS There were no significant differences in the early asthmatic responses during the 4 days; the mean maximum percent in FEV1 fall ranged between 19.5% and 22%. D5159 produced a slight inhibition of the LAR with maximum percent fall in FEV1 recorded as 28.8% +/- 5.0% for D5159 versus 34.1% +/- 4.8% for placebo (p < 0.05). There was a greater reduction recorded after administration of the two doses of budesonide. The mean LAR was 15.1% +/- 3.8% for 200 microg of budesonide and 11.2% +/- 2.3% for 800 microg of budesonide (p < 0.01 compared with placebo and D5159). The two doses of budesonide were not statistically different. Airway responsiveness to methacholine increased by 1.07 doubling doses 24 hours after allergen challenge. This increased airway responsiveness was slightly, but not significantly, reduced by the three active treatments (0.6 to 0.91 doubling doses). CONCLUSION The allergen-induced LAR model was able to differentiate a single dose of an active inhaled corticosteroid from placebo and a highly potent inhaled corticosteroid from a weak inhaled corticosteroid. The model did not differentiate between 2 fourfold doses of the highly active inhaled corticosteroid (at the doses used in this study), neither for the fall in FEV1 nor for the increase in airway hyperresponsiveness.

Single-dose desloratadine and montelukast and allergen-induced late airway responses

Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.

Metalloproteinase-9 in Induced Sputum Correlates with the Severity of the Late Allergen-Induced Asthmatic Response

Background: Asthma is characterized by airway inflammation and remodeling in which matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) play an important role. Allergen exposure activates the inflammatory/repair process in sensitized subjects. Induced-sputum analysis is a non-invasive method that allows the assessment of changes in inflammatory and remodeling mediators implicated in asthma. Objectives: To evaluate the changes in MMP-9 and its principal inhibitor (TIMP-1) in sputum and plasma of mild allergic asthmatic subjects after whole-lung allergen challenge. Methods: Induced sputum and blood samples were obtained at baseline, and 6 and 24 h after challenge. MMP-9 and TIMP-1 levels in sputum and plasma were measured by ELISA. Results: Allergen challenge increased the percentage of sputum eosinophils and MMP-9 levels 6 and 24 h after the challenge compared to baseline levels, but TIMP-1 levels did not vary significantly. A significant correlation was observed between MMP-9 levels at 6 h and the maximum percent fall in FEV1 during the late response. Throughout the study, MMP-9 levels correlated significantly with the number of neutrophils in sputum. Conclusions: This study shows that analysis of induced sputum is a useful tool to study the variations in MMP-9 and TIMP-1 levels following allergen challenge, therefore allowing to evaluate their role in allergen-induced airway damage and repair.

A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses.

RATIONALE Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids. OBJECTIVES We evaluated the effect of an inhaled nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses. METHODS Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 μg) once daily, budesonide 200 μg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6. MEASUREMENTS AND MAIN RESULTS FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 μg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 μg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated. CONCLUSIONS Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).

Perceived symptoms and discomfort during induced bronchospasm: the role of temporal adaptation and anxiety∗☆

Using a mixed within-between design, this study was designed to evaluate the sensorial and cognitive/evaluative aspects of bronchoconstriction induced by progressive methacholine inhalation. 25 asthmatic patients and 15 normal controls were given two consecutive bronchoconstriction tests, inducing a fall of > 30% of the forced expiratory volume in 1 sec (FEV1), which was measured after each inhalation of methacholine. Immediately before each FEV1 measurement, Ss rated perceived bronchial closing, discomfort of breathing and anxiety, as well as the need to use a bronchodilator. In addition to state-anxiety, after each bronchoconstriction test asthma symptoms were evaluated by means of a Free Symptom Report and the Asthma Symptom Checklist. The results show that during the first test, asthmatic patients perceived their symptoms more accurately than non-asthmatic controls. However, during the second test, asthmatic patients became less accurate, while normal controls increased their accuracy of symptom report. These changes were not parallelled for the Free Symptom Report or the Asthma Symptom Checklist. These results suggest that, depending on situational circumstances, patients rely on their cognitive schemata to report asthma symptoms. Need for bronchodilator use was related to perceived discomfort but not to actual or perceived bronchial closing. Clinical implications of this study are discussed.