Profile: Biomarkers in asthma management
Since the late 1990s, the total cost of asthma medication has dramatically increased, primarily driven by the introduction of combination inhalers, whereas the proportion of patients with asthma control has not increased during the same period. This indicates that symptom-based treatment with ‘catch-all’ medication (combination inhalers) is not the way forward. Rather, the view is now emerging that patients must be better phenotyped and segmented into subgroups, since asthma is a heterogeneous condition and not a uniform disease. Furthermore, overdiagnosis of asthma of approximately 30%, with unnecessarily high prescription of inhaled corticosteroid (ICS) treatment as a consequence, has been shown in surveys performed in primary healthcare, and, vice versa, the problem with poor treatment adherence in asthma is well recognised. To be able to make much-needed improvements of asthma management, the important role of biomarkers has been identified.
At present, FeNO is the most widely used biomarker in clinical practice. These measurements are highly standardised, and there have been numerous articles published on FeNO since the original description of its role in asthma. FeNO signals local Th2 cytokine-driven inflammation in the bronchial mucosa, primarily IL-4 and IL-13, and has been shown to predict clinical responsiveness to the introduction of ICS treatment. Furthermore, FeNO is reduced in a highly dose-dependent fashion in response to ICS treatment. It has recently been shown that FeNO-guided anti-inflammatory treatment in asthma reduces exacerbation rates in both adults and children compared to symptom-guided management.
FeNO is commonly regarded as a surrogate marker of eosinophilic inflammation. However, we have suggested that there may be a biological dissociation between FeNO and eosinophilic inflammation, since the eosinophil has a systemic origin whereas NO originates in resident cells in the airways: the bronchial epithelium. In contrast to the general belief, we have shown that FeNO and blood eosinophil (B-Eos) count are independent and additive predictors of asthma morbidity. We have also shown that aeroallergen and food allergen sensitisation, independently of each other, drive both FeNO and B-Eos count. This could explain the large heterogeneity in the relationship between these two markers in patients with asthma.
Our research is based on a number of population-based or clinical cohorts of subjects with asthma. A biobank has been built up with samples from these cohorts. Important examples are:
MIDAS (Minimally-Invasive Diagnostics in allergy and ASthma)
The MIDAS cohort comprises 411 patients with asthma (recruited from both primary and secondary care in Uppsala) and 121 random control subjects age 10-34 years. The baseline survey (MIDAS I) was performed in 2010-12, and a three-year follow-up survey is presently on-going (MIDAS II, 2013-15). To date, almost 200 out of 532 subjects have been examined in MIDAS II.
SPAIS (Screening Project Asthma In Schools)
The baseline examination of the SPAIS cohort was undertaken in 1998-99 and comprised 959 13 to 14-year-old schoolchildren examined in nine randomly chosen schools in Uppsala. A four-year follow-up was performed with the same questionnaires applied on the entire cohort and a clinic visit for a subgroup of subjects (n=374). We have now started a 15-year follow-up of this cohort (SPAIS III, 2014-16). The subjects have been contacted by mail and invited to a web-based questionnaire, and so far 422 out of 959 have responded, and we have started to recruit responders to a clinic visit (55 subjects have been examined to date).
NOAK (Optimisation of anti-inflammatory treatment in patients with atopic asthma by using exhaled NO)
The NOAK study is an interventional study in 187 adults with atopic asthma performed at 17 primary healthcare centres in the middle and south of Sweden. The patients were randomised to either FeNO-guided treatment or usual care, and were followed over one year and five visits (zero, two, four, eight and 12 months). Blood samples were taken at first and last visit.
Examples of on-going and planned research:
1. Evaluation of the added value of the combined use of a local and a systemic marker of the Th2/eosinophil type of inflammation
The preferred marker/s of systemic eosinophilic inflammation, for example B-Eos or serum eosinophilic cationic protein (S-ECP), will be evaluated with regard to possible additive information when used in combination with FeNO. In the MIDAS cohort, predictive effects of such a combination of biomarkers on asthma morbidity will be evaluated. Further, biobank material from the NOAK study will be used to evaluate the predictive effect of FeNO and an eosinophilic marker in combination on treatment responsiveness.
2. Component-resolved IgE-sensitisation profiles
In collaboration with Thermo Fisher Scientific, IgE sensitisation to available components of cat, horse and dog allergens will be determined in the MIDAS cohort. The ability of IgE sensitisation to certain allergen components to more accurately indicate a risk for asthma morbidity, compared with IgE sensitisation to the standard allergen extracts, will be studied.
3. Prognostic value of biomarkers
In the MIDAS cohort, we will study the short term (three years) prognostic value of biomarkers for changes in, for example, asthma control, lung function, and IgE sensitisation, as well as the predictive value for exacerbations occurring in the interval between the examinations. In the SPAIS cohort, we aim to evaluate the long term (15 years) prognostic value of FeNO for the development of respiratory symptoms, lung function, and IgE sensitisation going from adolescence to adulthood.
4. Characteristics of non-atopic asthma in young subjects
In the MIDAS cohort, we have found that patients with non-atopic asthma reporting food hypersensitivity have poorer asthma control than atopic patients reporting food hypersensitivity as well as patients not reporting food hypersensitivity. This group of non-atopic patients will be further characterised and compared with the other phenotypes with regard to inflammatory profile (Th2- and non-Th2-driven inflammation) and, for example, antibodies against food antigens (IgE, IgG and IgA). An inflammation array (92 inflammatory molecules, Olink, Sweden) will be applied to compare this subgroup of patients with age and gender-matched atopic asthma patients.
5. FeNO in asthma management in primary care
For further evaluation of FeNO in asthma management, we plan for a European multicentre study. This study will be in collaboration with Aerocrine, Sweden, and will involve clinical researchers in the UK, Sweden, France, Germany, Spain, the Netherlands and Italy. The consortium will seek funding within the SME Instrument in Horizon 2020.
Kjell Alving
Professor of Respiratory Pharmacology
Department of Women’s and Children’s Health, Uppsala University
Uppsala University Hospital
SE-751 85 Uppsala
Sweden
+46 70 659 8870
