Phenotyping of severe asthma in a clinical context

Severe asthma is a chronic heterogeneous inflammatory disease characterized by several clinical phenotypes and molecular endotypes. Although it affects a relatively small proportion of the asthma population (approximately 4%-10%), with an even smaller proportion of these having severe uncontrolled eosinophilic asthma, it accounts for > 50% of the costs attributed to the disease. Despite the availability of modern medicines and improvements in certain outcomes, severe asthma is still a cause of mortality. Although it is known that severe asthma is driven by type 2 inflammation in most cases, and we now have the possibility to use specific biological therapies targeting this particular type of inflammation, many patients are still suboptimally controlled due to the heterogenous nature of this disease with its multiple subphenotypes. There is, therefore, an unmet need to characterize and classify these patients with a view to improve therapy and reduce costs on a global scale. Furthermore, selection of the most appropriate biologic and the best clinical outcomes and biomarkers with which to monitor response to therapy, are still issues of debate and the subject of ongoing research. Three clinical severe asthma studies are included in this thesis, the overall aim of which was to provide an increased understanding of the clinical features and treatment effects associated with the different sub-phenotypes of severe asthma. A specific focus was also to validate different clinical outcomes and assess their importance for the management of asthma. The three studies address these aims in different ways including an epidemiological investigation (Paper I), a pharmacological assessment of the drugs used to treat asthma as well as their side effects and relationship with asthma severity (Paper II) and a clinical intervention applied in a “real-life” setting, including a preliminary meta-analysis with the objective to develop a new method for assessment of response to therapy (Paper III). Several important observations were made in Paper I. The results of this study revealed differences in clinical characteristics, lifestyle factors and treatment patterns among severe asthmatics in Europe, confirming the heterogeneity of this disease. Moreover, the severe asthma definition in current guidelines did not correspond to the characteristics of real-world severe asthmatics, and the definitions also differed between countries. Finally, Paper I emphasized the importance of harmonizing severe asthma registries throughout Europe, and the need for long-term follow-up of this group of patients. In Paper II was done analysis of data from 478 well characterized asthmatics and 98 healthy controls in the U-BIOPRED study. Paper II shows that severe asthmatics have significant suppression of androgens and cortisol compared to patients with mild-to-moderate asthma and healthy control according to extensive analysis of urinary endogenous and exogenous steroids. This suppression is more pronounced in women compared to men. Moreover, the data show that this adrenal suppression is depended on the level of treatment with exogenous corticosteroids. Thus, our results provide support to the hypothesis that this relative deficiency in androgen levels during steroid treatment that is disproportional greater in women compared to men may partly explain gender differences in the severity of asthma and prevalence. Finally, our study supports that reduction of high dose inhaled corticosteroids (ICS), and especially the taper of oral corticosteroids (OCS) should be a clinical goal in order to reduce the side effects of corticosteroids. In Paper III, we modified a quantitative algorithm that was originally developed in a European collaboration to assess response to therapy and evaluate efficacy, and then tested this strategy in patients with severe asthma undergoing treatment with the biologic mepolizumab. The method was able to quantify response to an expensive biological treatment and identify four groups with different degrees of response to mepolizumab: super response, substantial response, sufficient response, and non-response. The super responder group had the greatest improvement in lung function, asthma quality of life questionnaire, asthma control questionnaire and the highest reductions in exacerbations and OCS use, whereas the nonresponders lost asthma control, discontinued mepolizumab treatment and switched to other biologics. This new, quantitative algorithm was shown to provide a more individualized assessment of treatment response and identified non-responders in need of revised treatment. Further, this method can be implemented in clinical practice for greater precision in early clinical decision-making regarding the use of biological therapy. In conclusion, the three clinical studies included in the thesis have contributed to an increased understanding of the clinical phenotypes of severe asthma. The experiences accumulated during this work allow for some general implications. For example, longitudinal, prospective studies carried out in a real-world setting are important for evaluation of response to treatment with new drugs since the differing responses of well-characterized and phenotyped patients can reveal clinical sub-phenotypes and their relationship to underlying molecular mechanisms. The utility of different clinical outcomes could be validated and their importance for asthma management assessed. Clinical studies also provide an opportunity to investigate requirements for improved management and care of severe asthmatics. Patient-centred research contributes to a better understanding of patient needs, and thereby facilitates refined assessment of clinical response to treatment

Business alliances in the economy of EU countries

The activities of business alliances in the EU are being transformed by the aid of the policy implementation of industrial alliances development, which provides for a wide network formation of stakeholders in reducing the dependence of member states on raw materials of third countries. The purpose of the academic paper lies in assessing empirically the business alliances effectiveness in the EU based on the case studies analysis on creating strategic alliances. Methodology. The case method has been used in the course of the research in order to analyse the activities and effects of business alliances within the established network for cooperation of the European Raw Materials Alliance (ERMA). The results demonstrate the uncertainty in the strategic business alliances effectiveness in the EU; it is difficult to assess the potential quantitative effect from the company’s resources synergy – alliance members in the short-term prospects. Despite the well-established principles, the choice of the alliance management form as joint venture, the company’s market value has decreased. The advantages of the business alliance include the supply chain diversification of of raw materials from Third World countries to EU countries for industrial production. The theoretical and practical research value lies in supplementing the transaction costs theory and the theory of resources, explaining the business alliances creation. In practice, companies - members of business alliances combine the features of both theories in order to take into accounts both costs and synergies from resource integration

Definitions of non-response and response to biological therapy for severe asthma: a systematic review

Background: Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma. Methods: We searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken. Results: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated “very low” to “low” for quality of measurement properties and none met all quality standards. Conclusions: This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics

Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids

Rationale: patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure.Methods: urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study.Measurements and main results: the concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were Conclusion The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma

Eosinophilic airway diseases : basic science, clinical manifestations and future challenges

Eosinophils have a broad range of functions, both homeostatic and pathological, mediated through an array of cell surface receptors and specific secretory granules that promote interactions with their microenvironment. Eosinophil development, differentiation, activation, survival and recruitment are closely regulated by a number of type 2 cytokines, including interleukin (IL)-5, the key driver of eosinophilopoiesis. Evidence shows that type 2 inflammation, driven mainly by interleukin (IL)-4, IL-5 and IL-13, plays an important role in the pathophysiology of eosinophilic airway diseases, including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Several biologic therapies have been developed to suppress type 2 inflammation, namely mepolizumab, reslizumab, benralizumab, dupilumab, omalizumab and tezepelumab. While these therapies have been associated with clinical benefits in a range of eosinophilic diseases, their development has highlighted several challenges and directions for future research. These include the need for further information on disease progression and identification of treatable traits, including clinical characteristics or biomarkers that will improve the prediction of treatment response. The Nordic countries have a long tradition of collaboration using patient registries and Nordic asthma registries provide unique opportunities to address these research questions. One example of such a registry is the NORdic Dataset for aSThmA Research (NORDSTAR), a longitudinal population-based dataset containing all 3.3 million individuals with asthma from four Nordic countries (Denmark, Finland, Norway and Sweden). Large-scale, real-world registry data such as those from Nordic countries may provide important information regarding the progression of eosinophilic asthma, in addition to clinical characteristics or biomarkers that could allow targeted treatment and ensure optimal patient outcomes

Eosinophilic airway diseases: basic science, clinical manifestations and future challenges

Eosinophils have a broad range of functions, both homeostatic and pathological, mediated through an array of cell surface receptors and specific secretory granules that promote interactions with their microenvironment. Eosinophil development, differentiation, activation, survival and recruitment are closely regulated by a number of type 2 cytokines, including interleukin (IL)-5, the key driver of eosinophilopoiesis. Evidence shows that type 2 inflammation, driven mainly by interleukin (IL)-4, IL-5 and IL-13, plays an important role in the pathophysiology of eosinophilic airway diseases, including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Several biologic therapies have been developed to suppress type 2 inflammation, namely mepolizumab, reslizumab, benralizumab, dupilumab, omalizumab and tezepelumab. While these therapies have been associated with clinical benefits in a range of eosinophilic diseases, their development has highlighted several challenges and directions for future research. These include the need for further information on disease progression and identification of treatable traits, including clinical characteristics or biomarkers that will improve the prediction of treatment response. The Nordic countries have a long tradition of collaboration using patient registries and Nordic asthma registries provide unique opportunities to address these research questions. One example of such a registry is the NORdic Dataset for aSThmA Research (NORDSTAR), a longitudinal population-based dataset containing all 3.3 million individuals with asthma from four Nordic countries (Denmark, Finland, Norway and Sweden). Large-scale, real-world registry data such as those from Nordic countries may provide important information regarding the progression of eosinophilic asthma, in addition to clinical characteristics or biomarkers that could allow targeted treatment and ensure optimal patient outcomes

Prevalence and management of severe asthma in the Nordic countries : findings from the NORDSTAR cohort

Background Real-life evidence on prevalence and management of severe asthma is limited. Nationwide population registries across the Nordic countries provide unique opportunities to describe prevalence and management patterns of severe asthma at population level. In nationwide register data from Sweden, Norway and Finland, we examined the prevalence of severe asthma and the proportion of severe asthma patients being managed in specialist care. Methods This is a cross-sectional study based on the Nordic Dataset for Asthma Research (NORDSTAR) research collaboration platform. We identified patients with severe asthma in adults (aged >= 18 years) and in children (aged 6-17 years) in 2018 according to the European Respiratory Society/American Thoracic Society definition. Patients managed in specialist care were those with an asthma-related specialist outpatient contact (only available in Sweden and Finland). Results Overall, we identified 598 242 patients with current asthma in Sweden, Norway and Finland in 2018. Among those, the prevalence of severe asthma was 3.5%, 5.4% and 5.2% in adults and 0.4%, 1.0%, and 0.3% in children in Sweden, Norway and Finland, respectively. In Sweden and Finland, 37% and 40% of adult patients with severe asthma and two or more exacerbations, respectively, were managed in specialist care; in children the numbers were 56% and 41%, respectively. Conclusion In three Nordic countries, population-based nationwide data demonstrated similar prevalence of severe asthma. In children, severe asthma was a rare condition. Notably, a large proportion of patients with severe asthma were not managed by a respiratory specialist, suggesting the need for increased recognition of severe asthma in primary care.Peer reviewe

Severe asthma trajectories in adults : findings from the NORDSTAR cohort

Background: There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma. Methods: We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018. Results: Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma. Conclusions: Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma

Definitions of non-response and response to biological therapy for severe asthma: a systematic review

Background: biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma.Methods: we searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken.Results: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated "very low" to "low" for quality of measurement properties and none met all quality standards.Conclusions: this is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.</p