Phenotyping of severe asthma in a clinical context

Abstract

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.