Bronchoprovocation studies to define mechanisms in asthma and airway inflammation

Bronchial provocations with a variety of stimuli have been widely used over the past 70 years in both asthma research as well as in daily clinical praxis in order to aid the physician to establish the asthma diagnosis. In research, the bronchoprovocation model represents an excellent tool to better understand asthma pathophysiology, and to assess the effects of different interventions and new investigational therapies. Most of the currently approved asthma therapeutic options have shown efficacy in previous studies using the bronchoprovocation setting. In the current thesis, a range of bronchial provocations was performed prior to and after treatment with pharmacological interventions with different mode of actions. Responses were measured in the airways in the form of induced bronchoconstriction and airway inflammation (sputum cell counts), as well as in other matrices (skin, blood, urine). For the first time, it was shown that treatment with the combination of budesonide-formoterol (bud/form) in a single inhaler taken three to four times per week provided the same magnitude of protection against exercise-induced bronchoconstriction (EIB) as to regular treatment with a low dose of budesonide. Moreover, subjects who received monotherapy with the short acting β2 agonist (SABA) terbutaline had no protection against EIB over time. These results question the place of SABA monotherapy in asthma treatment even for subjects with mild asthma. It is recommended to replace SABA monotherapy with intermittent use of bud/form, which can also be an alternative option to regular treatment with low dose inhaled corticosteroids (ICS). Furthermore, using an allergen bronchoprovocation model, it was demonstrated that treatment with the second-generation anti-IgE monoclonal antibody QGE031 (ligelizumab) elicited an inhibition of the early allergic response (EAR) that was three times greater than what was achieved by the currently approved anti-IgE treatment with omalizumab. In addition, the data showed that there were important differences in the allergen response in the airways compared to the skin during QGE031 therapy; the highest dose of QGE031 consistently supressed allergen induced skin test responses that persisted six weeks after the last dose was given, while there was a variable effect on the airway response that did not last six weeks after the last dose. These results elucidate the complexity of the IgE pathway and the different kinetics and tissue responses to anti-IgE therapy. Finally, this thesis answered some important questions about the role of cysteinyl leukotrienes (CysLTs) and in particular leukotriene E4 (LTE4) in asthma. The data showed that treatment with the potent CysLT1 receptor antagonist montelukast completely abolished the bronchoconstriction elicited by LTE4 inhalation in subjects with mild asthma. Urine was collected during the LTE4 provocations for analysis of lipid mediator excretion, which led to the serendipitous discovery of increased urinary excretion of metabolites of prostaglandin (PG) D2, as well as other lipid mediators after LTE4 inhalation. These novel findings add a new dimension, namely that LTE4, in addition to a direct bronchoconstrictive action, can also activate both the mast cell as well as other cells to produce secondary responses that can amplify or modify its primary effect. Thus, this thesis demonstrates that carefully planned and conducted studies using bronchial provocations in combination with various pharmacological interventions, can elucidate important mechanisms in asthma pathogenesis and reveal potential new targets for treatmen

Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction

Background In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting β2 agonists (SABAs) on demand. Objective The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. Methods Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg)  + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Results After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI −10.3 to −3.0) and 5.4% (−8.9 to −1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; −2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. Conclusions The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma

Allergen provocation tests in respiratory research: building on 50 years of experience

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review

Allergen provocation tests in respiratory research: building on 50 years of experience

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review

Allergen provocation tests in respiratory research: building on 50 years of experience

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review

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

The effect of the COVID-19 pandemic on severe asthma care in Europe: will care change for good?

Background: The COVID-19 pandemic has put pressure on health-care services forcing the reorganisation of traditional care pathways. We investigated how physicians taking care of severe asthma patients in Europe reorganised care, and how these changes affected patient satisfaction, asthma control and future care. Methods: In this European-wide cross-sectional study, patient surveys were sent to patients with a physician-diagnosis of severe asthma, and physician surveys to severe asthma specialists between November 2020 and May 2021. Results: 1101 patients and 268 physicians from 16 European countries contributed to the study. Common physician-reported changes in severe asthma care included use of video/phone consultations (46%), reduced availability of physicians (43%) and change to home-administered biologics (38%). Change to phone/video consultations was reported in 45% of patients, of whom 79% were satisfied or very satisfied with this change. Of 709 patients on biologics, 24% experienced changes in biologic care, of whom 92% were changed to home-administered biologics and of these 62% were satisfied or very satisfied with this change. Only 2% reported worsening asthma symptoms associated with changes in biologic care. Many physicians expect continued implementation of video/phone consultations (41%) and home administration of biologics (52%). Conclusions: Change to video/phone consultations and home administration of biologics was common in severe asthma care during the COVID-19 pandemic, and was associated with high satisfaction levels in most but not all cases. Many physicians expect these changes to continue in future severe asthma care, though satisfaction levels may change after the pandemic