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Understanding asthma phenotypes: going beyond the atopic/non-atopic paradigm

Periodic Reporting for period 3 - AsthmaPhenotypes (Understanding asthma phenotypes: going beyond the atopic/non-atopic paradigm)

Reporting period: 2019-01-01 to 2020-06-30

Most research has treated asthma as an “allergic disease”, but we have previously shown that less than one-half of asthma cases involve allergic mechanisms, and that the association between allergy and asthma is much weaker than in low-and-middle income countries than in high income countries. Research is needed into better ways of defining the different types of asthma, and to understand the balance between the types of asthma in areas with different risk factors and different levels of asthma prevalence. This is needed to enable low-and-middle income countries to avoid the asthma epidemic that has occurred in high-income countries. Better characterisation of the different types of asthma is also needed to enable better management and prevention of asthma in both high and low-and-middle income countries. For example, about one-half of asthmatics appear to have ‘non-allergic asthma’ and this does not seem to respond to the standard medications (particularly inhaled corticosteroids) as well as ‘allergic asthma’ does, so new methods of treatment need to be developed.

I am therefore conducting a multi-country study to look at different types of asthma in a variety of settings: high and low asthma prevalence, and high income and low-middle income countries. This is going beyond previous work both by including low-middle income countries (and high/low prevalence centres), and by collecting much more detailed biological information than has been collected previously. By identifying risk factors that are common to the different types of asthma in these different settings, the study will help to identify what causes asthma and this will inform both prevention and treatment. The study is being conducted in five centres with a range of asthma prevalence levels and exposures (and a likely range of prevalence of the different types of asthma): (i) Bristol, UK; (ii) Wellington, New Zealand; (iii) Salvador, Brazil; (iv) Ecuador; and (v) Entebbe, Uganda. In each centre, we are recruiting 200 asthmatics and 50 non-asthmatics.

The objectives of this study are to combine detailed biomarker and clinical information to: (i) better understand and characterise asthma phenotypes in high income countries (HICs) and low- and middle-income countries (LMICs), and in high and low prevalence centres; (ii) compare their characteristics, including clinical severity; (iii) assess the risk factors for each phenotype; and (iv) assess how the distributions of phenotypes differs between high prevalence and low prevalence centres.
This research is important because it will lead to a better understanding of the causes of asthma, and raise the potential to prevent the global epidemic of asthma, which has occurred in high-income countries, and is beginning to occur in low-and-middle income countries.
The AsthmaPhenotypes study started on 1 January 2016, and is being conducted in five centres in the United Kingdom, New Zealand, Brazil, Ecuador and Uganda.
Detailed information is being collected from 200 participants with asthma and 50 non-asthmatics in each centre, including sputum and nasal samples, blood samples, lung function and skin prick testing. Children and adolescents will be enrolled in all centres except Bristol where participants are 26-27 years old but who all have detailed information on asthma throughout their childhood.
During the first 18 months of this project, we developed detailed protocols for data and sample collection and processing of samples. Training sessions were held to ensure that staff in each centre were familiar with the procedures in the protocols, in particular for sputum induction. We prepared a study protocol paper, which has recently been published in ERJ Open Research. Several other related asthma and methodological papers have also been published.
Following a period of protocol development, training and piloting of procedures, data collection was completed in June 2019. Laboratory analyses and data analyses are in progress.
We have made progress beyond the state of the art in several respects.
Firstly, this is the first time that techniques such as sputum induction have been used to make comparisons between low-and-middle-income countries and high-income countries. Although the individual and specific methods used in this study have each been used in previous studies, this study is novel in combining a wide variety of clinical methods and other biomarkers in the same individuals to provide a comprehensive dataset, and by including centres in both high income and low- and middle-income countries. The nasal lavage technique has not previously been used in large-scale, multi-centre studies. It has taken a considerable amount of work to train the staff in the various centres, and to ensure standardised methods of data collection.
Secondly, we have gone beyond the state of the art with respect to methods for defining and assessing disease phenotypes, and to infer causality. This new work has involved collaborations with colleagues who are experts in causal inference methods, and philosophy (as applied to medical research). This work has resulted in four methodological publications to date, as well as the conduct of several short courses in epidemiological methods and causal inference.
Thirdly, we are working on methodological techniques that will go beyond the state of the art in terms of bioinformatics methods for combining complex high-dimensional data for defining and analysing disease phenotypes. We have had initial meetings with colleagues in London and Barcelona, and we are in the process of creating a network of researchers who are using similar data to study phenotypes of asthma, and also of other diseases (including eczema, and other allergy-related diseases).
The expected future results include: (i) new characterisations of asthma and its phenotypes in high-income and low-and-middle income countries; (ii) better understanding of the role of ‘omics data, and bioinformatics methods in identifying and defining these phenotypes; (iii) potentially improved understanding of asthma aetiology, with the subsequent potential for new treatments and preventive measures to be developed.