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

Periodic Reporting for period 4 - AsthmaPhenotypes (Understanding asthma phenotypes: going beyond the atopic/non-atopic paradigm)

Reporting period: 2020-07-01 to 2021-09-30

What is the problem / issue being addressed?
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. I therefore conducted a multi-country study to look at different types of asthma in a variety of settings. 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 has been conducted in five centres with a range of asthma prevalence levels and types: (i) Bristol, UK; (ii) Wellington, New Zealand; (iii) Salvador, Brazil; (iv) Ecuador; and (v) Entebbe, Uganda.

Why is it important for society?
This research will lead to a better understanding of the causes of asthma, and raise the potential to prevent the global epidemic of asthma, that has occurred in high-income countries, and is beginning to occur in low-and-middle income countries. In particular, we need better ways of defining the different types of asthma, and we need 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.

What are the overall objectives?
The objectives of this study were 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.
The AsthmaPhenotypes study started on 1 January 2016, and was conducted in five centres in the United Kingdom, New Zealand, Brazil, Ecuador and Uganda. Detailed information was collected from asthmatics and non-asthmatics across the centres, including sputum and nasal samples, blood samples, lung function and skin prick testing. Children and adolescents were enrolled in all centres except Bristol where participants are 26-27 years old but who all have detailed information on asthma throughout their childhood.

Following a period of protocol development, training and piloting of procedures, data collection commenced and was completed in May 2019. In the following two years, we processed the collected samples. This included reading of the sputum slides, reading of the nasal lavage slides, processing of the serum samples for serum IgE, testing of the supernatant samples (from sputum induction), microbiome analyses (sputum plugs) and epigenetic analyses (sputum plugs).

We recruited 998 asthmatics and 356 non-asthmatics in total. Sputum induction testing was conducted, with 87% providing a sputum sample, ranging from 74% (Brazil) to 93% (United Kingdom); of these, 72% were countable. The proportion of asthmatics classified as eosinophilic or mixed granulocytic asthma (i.e. eosinophilic asthma (EA)) was 39% (95% confidence interval 35%-43%) overall: 35% in Brazil, 32% in Ecuador, 50% in New Zealand, 33% in Uganda, and 34% in the United Kingdom. The non-eosinophilic asthmatics (NEA) had similar severity/control to the eosinophilic asthmatics (EA). Of the 61% (95% CI 57%-65%) of cases with NEA, 50% showed no signs of inflammation (paucigranulocytic), with 11% having neutrophilic inflammation. We are now comparing these inflammatory phenotypes according to their results for the other laboratory tests (serum IgE supernatant, microbiome and epigenetics).

The importance of non-eosinophilic asthma was highlighted at an Academia Europea/Asthma UK meeting of invited experts that I attended in Cardiff in November 2018, in which our preliminary AsthmaPhenotypes findings were discussed.
This is the first time that sputum induction has been used in a standardised manner to compare asthma inflammatory phenotypes in high income countries (HICs) and low-and-middle-income countries (LMICs) and confirms that most cases are non-eosinophilic. This has potentially major implications for asthma prevention and management in both of these contexts, and supports the urgent need to recognise that asthma is a heterogeneous condition, and to develop new prevention strategies and new therapies which target non-eosinophilic asthma.

In addition, we have found important differences between those with EA and those with NEA, as defined by sputum inflammatory phenotypes. These not only include differences in nasal inflammatory phenotypes, and serum IgE. Also, preliminary analysis shows levels of IL-1b, IL-8 and neutrophil elastase were higher in participants with NEA than in those with EA, suggesting a potential role for neutrophils. As expected, periostin levels were higher in EA than NEA. NGF-b was more often undetectable in NEA than EA. Further analysis may highlight potential mechanisms and pathways associated with different asthma phenotypes.

Our finding of a high prevalence of neutrophilic asthma in the Uganda centre is also novel and warrants further investigation, including analysis of risk factors by inflammatory phenotype which is underway.

These findings form the basis for my new ERC Advanced Grant (CAMERA) which was recently funded, and which builds on the AsthmaPhenotypes study. This new project is examining risk factors and mechanisms for non-eosinophilic asthma in children in four of the AsthmaPhenotypes centres: Brazil, Ecuador, Uganda, and New Zealand.
Sputum inflammmatory phenotypes by country