What are the most recent advances in biomarkers for asthma?

Asthma affects millions worldwide, including around 12% of children aged 6–7.¹ Although symptoms for all asthma patients share a common set of traits (chest tightness, shortness of breath, wheezing, etc.), the underlying disease mechanisms of this chronic inflammatory condition can vary between patients. This means that the selections for treating asthma become highly individualized.

A major distinction between asthma cases is the type of immune cells that lead to inflammation: majority eosinophilic or neutrophilic. Eosinophilic cases are typically responsive to glucocorticoid steroid treatments, whereas cases dominated by neutrophils demonstrate poor response to steroids.

Asthma diagnosis is based on clinical history, physical examination, and lung function. However, the currently available diagnostic methods do not facilitate direct asthma diagnosis, nor can they differentiate between phenotypes; therefore, a ‘trial and error’ approach is often the way clinicians proceed with treatment.

Inappropriate treatments may be prescribed, which can result in unnecessary spending for healthcare systems with an increased risk of exacerbations for the patient and periods of subpar disease control.

Hundreds of volatile organic compounds (VOCs) are contained in human breath, several of which originate locally in the respiratory tract because bodily processes such as lipid peroxidation which could potentially be new biomarkers for asthma. The underlying immunological mechanisms and pathophysiology of asthma can produce VOCs; therefore, using these VOCs as biomarkers could eliminate the need for a trial-and-error approach.

Image Credit: Owlstone Medical Ltd

Asthma is among the most extensively studied respiratory diseases in terms of the VOCs in breath. This is likely due to the significance of asthma as a common chronic respiratory condition with a considerable impact on quality of life, and the potential clinical benefits that breath tests could offer.

Fractional Exhaled Nitric Oxide (FeNO) is the one-breath test currently used in asthma diagnosis. This test is usually only used to support a diagnosis of asthma rather than serve as a conclusive biomarker, as there are cases of asthma, particularly eosinophilic asthma, where FeNO may be low.^2,3

Therefore, acquiring deeper insights as to how levels of other informative volatiles in breath fluctuate in asthma patients could bring about the development of further diagnostic tests. These tests could provide more detailed information about specific asthma phenotypes and determine underlying physiology in an individual’s respiratory tract.

Given the considerable variability of volatile compounds among the human population, studies that take an untargeted approach without suitable controls can easily produce false positive hits when determining candidate biomarkers. Therefore, it is vital to cross-validate the findings of VOC composition related to asthma across the literature and identify which studies found compounds highly likely to be genuine candidate signals associated with asthma pathophysiology, as opposed to background spurious signals.

To this end, Owlstone conducted a literature review and ran it against its own internal data to summarize the most promising VOC biomarkers for asthma (covering a broad range of studies across different asthma severities, age groups, and phenotypes in the first incidence) for this case study.

As of 6 March 2024, around 200 unique VOCs associated with asthma were identified from the literature and Owlstone’s internal data. These compounds can be sorted into useful categories.^4-26

The first group incorporates asthma-associated VOCs in Owlstone’s Breath Biopsy VOC Atlas classified as “on-breath” (group 1), and the second group are those VOCs in Owlstone’s VOC Atlas categorized as “off-breath” (group 2).

Owlstone’s VOC Atlas contains VOCs that have been evaluated meticulously for their presence in the breath (“on-breath”) in a controlled population of heterogeneous volunteers without any specific pathophysiology as opposed to those originating from environmental contaminants. All VOCs have been tested using stringent validation methods against standard references to confirm their identities.

This means that the on-breath compounds can be associated with a normal, healthy variation in the population. In contrast, the off-breath compounds in the VOC Atlas do not appear in the breath of individuals considered healthy frequently enough, or in high enough concentration to be considered part of normal variation.

This means that off-breath compounds in the VOC Atlas that occur at detectable levels in the breath of those with asthma makes them promising markers to conduct further investigations as potential breath VOC biomarkers of asthma.

A total of 87 of around 200 compounds can be found in the VOC Atlas, of which 86% were identified in several papers as being associated with asthma. Of the compounds identified that do not appear in the VOC Atlas, it can be assumed that they contain the key compounds that can be separated with confidence from spuriously significant compounds, as they were only mentioned in a single paper across the literature.

Of the combined VOC dataset, 35 group 1 compounds and 52 group 2 compounds appeared in an altered state in the breath signature of asthma patients. The increase in the chemical classes of the compounds in asthmatic patients who were also group 2 is likely to offer insights into which biological mechanism produces them.

Image Credit: Owlstone Medical Ltd

In comparison to group 1 compounds, there were 31% more alkanes, 10% more aldehydes, and 10% more cyclic hydrocarbons group 2 compounds. This is a strong indicator that lipid peroxidation is a leading source of the altered volatile signature of the breath of asthmatic patients.

Chronic inflammation is a defining characteristic of asthma, a state that leads to oxidative stress in the tissues of the respiratory tract. This produces reactive oxygen species that may react with unsaturated fatty acids in the cell, and the consequent release of distinctive volatile compounds like alkanes.²⁷

Although there is a known association between lipid peroxidation and a number of inflammatory diseases, the various lipid compositions and redox enzyme complements of different cell types can produce a unique set of VOC lipid peroxidation products.

In asthma, the inflammatory process results from the interactions between leukocytes, epithelial and stromal cells of the respiratory tract, producing unique patterns of volatiles in the patient’s breath.²⁸

Consequently, these group 2 compounds are strong candidates for use as biomarkers to further investigate the asthma-related pathophysiology that causes their altered states and levels in the breath.

More work needs to be done to link the characteristic changing levels of these compounds in the breath of asthma patients, and the underlying mechanisms responsible. In the long term, the aim is to validate these biomarkers and eventually translate them into practical breath tests for asthma in clinical use.

Owlstone’s Breath Biopsy VOC Atlas can be used for breath research studies as part of its Breath Biopsy OMNI^® service to improve and accelerate breath biomarker identification and validation.

To discover more information about breath biomarkers for asthma and other potential research studies involving VOCs, please do not hesitate to contact Owlstone today.

References and further reading

1. Prevalence | Background information | Asthma | CKS | NICE [Internet]. [cited 2023 Aug 16]. Available from: https://cks.nice.org.uk/topics/asthma/background-information/prevalence/
2. Stuehr DJ. Mammalian nitric oxide synthases. Biochim Biophys Acta. 1999 May 5;1411(2–3):217–30.
3. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FeNO) for Clinical Applications. Am J Respir Crit Care Med. 2011 Sep 1;184(5):602–15.
4. Alahmadi FH, Wilkinson M, Keevil B, Niven R, Fowler SJ. Short- and medium-term effect of inhaled corticosteroids on exhaled breath biomarkers in severe asthma. J Breath Res. 2022 Jul;16(4):047101.
5. Brinkman P, van de Pol MA, Gerritsen MG, Bos LD, Dekker T, Smids BS, et al. Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma. Clin Exp Allergy. 2017 Sep;47(9):1159–69.
6. Brinkman P, Ahmed WM, Gómez C, Knobel HH, Weda H, Vink TJ, et al. Exhaled volatile organic compounds as markers for medication use in asthma. Eur Respir J. 2020 Feb;55(2):1900544.
7. Dragonieri S, Schot R, Mertens BJA, Le Cessie S, Gauw SA, Spanevello A, et al. An electronic nose in the discrimination of patients with asthma and controls. J Allergy Clin Immunol. 2007 Oct;120(4):856–62.
8. Gahleitner F, Guallar-Hoyas C, Beardsmore CS, Pandya HC, Thomas CP. Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath. Bioanalysis. 2013 Sep;5(18):2239–47.
9. Ibrahim W, Wilde MJ, Cordell RL, Richardson M, Salman D, Free RC, et al. Visualization of exhaled breath metabolites reveals distinct diagnostic signatures for acute cardiorespiratory breathlessness. Science Translational Medicine. 2022 Nov 16;14(671):eabl5849.
10. Ibrahim B, Basanta M, Cadden P, Singh D, Douce D, Woodcock A, et al. Non-invasive phenotyping using exhaled volatile organic compounds in asthma. Thorax. 2011 Sep;66(9):804–9.
11. Klaassen EMM, van de Kant KDG, Jöbsis Q, van Schayck OCP, Smolinska A, Dallinga JW, et al. Exhaled biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age. Am J Respir Crit Care Med. 2015 Jan 15;191(2):201–7.
12. Awano S, Takata Y, Soh I, Yoshida A, Hamasaki T, Sonoki K, et al. Correlations between health status and OralChromaTM-determined volatile sulfide levels in mouth air of the elderly. J Breath Res. 2011 Sep;5(4):046007.
13. Caldeira M, Barros AS, Bilelo MJ, Parada A, Câmara JS, Rocha SM. Profiling allergic asthma volatile metabolic patterns using a headspace-solid phase microextraction/gas chromatography based methodology. Journal of Chromatography A. 2011 Jun 17;1218(24):3771–80.
14. Caldeira M, Perestrelo R, Barros AS, Bilelo MJ, Morête A, Câmara JS, et al. Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography. J Chromatogr A. 2012 Sep 7;1254:87–97.
15. Dallinga JW, Robroeks CMHHT, van Berkel JJBN, Moonen EJC, Godschalk RWL, Jöbsis Q, et al. Volatile organic compounds in exhaled breath as a diagnostic tool for asthma in children. Clin Exp Allergy. 2010 Jan;40(1):68–76.
16. Meyer N, Dallinga JW, Nuss SJ, Moonen EJC, van Berkel JJBN, Akdis C, et al. Defining adult asthma endotypes by clinical features and patterns of volatile organic compounds in exhaled air. Respir Res. 2014 Nov 28;15(1):136.
17. Monedeiro F, Monedeiro-Milanowski M, Ratiu IA, Brożek B, Ligor T, Buszewski B. Needle Trap Device-GC-MS for Characterization of Lung Diseases Based on Breath VOC Profiles. Molecules. 2021 Jan;26(6):1789.
18. Paredi P, Kharitonov SA, Barnes PJ. Elevation of Exhaled Ethane Concentration in Asthma. Am J Respir Crit Care Med. 2000 Oct;162(4):1450–4.
19. Robroeks CM, Berkel JJ van, Jöbsis Q, Schooten FJ van, Dallinga JW, Wouters EF, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. European Respiratory Journal. 2013 Jul 1;42(1):98–106.
20. Schleich FN, Zanella D, Stefanuto PH, Bessonov K, Smolinska A, Dallinga JW, et al. Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma. Am J Respir Crit Care Med. 2019 Aug 15;200(4):444–53.
21. Sharma R, Zang W, Zhou M, Schafer N, Begley LA, Huang YJ, et al. Real Time Breath Analysis Using Portable Gas Chromatography for Adult Asthma Phenotypes. Metabolites. 2021 May;11(5):265.
22. Smolinska A, Klaassen EMM, Dallinga JW, Kant KDG van de, Jobsis Q, Moonen EJC, et al. Profiling of Volatile Organic Compounds in Exhaled Breath As a Strategy to Find Early Predictive Signatures of Asthma in Children. PLOS ONE. 2014 Apr 21;9(4):e95668.
23. Sola-Martínez RA, Lozano-Terol G, Gallego-Jara J, Morales E, Cantero-Cano E, Sanchez-Solis M, et al. Exhaled volatilome analysis as a useful tool to discriminate asthma with other coexisting atopic diseases in women of childbearing age. Sci Rep. 2021 Jul 5;11(1):13823.
24. Vliet DV, Smolinska A, Jöbsis Q, Rosias PPR, Muris JWM, Dallinga JW, et al. Association between exhaled inflammatory markers and asthma control in children. J Breath Res. 2016 Feb;10(1):016014.
25. Vliet D van, Smolinska A, Jöbsis Q, Rosias P, Muris J, Dallinga J, et al. Can exhaled volatile organic compounds predict asthma exacerbations in children? J Breath Res. 2017 Mar;11(1):016016.
26. Shahrokny P, Maison N, Riemann L, Ehrmann M, DeLuca D, Schuchardt S, et al. Increased breath naphthalene in children with asthma and wheeze of the All Age Asthma Cohort (ALLIANCE). J Breath Res. 2023 Oct 12;18(1).
27. Ratcliffe N, Wieczorek T, Drabińska N, Gould O, Osborne A, Costello BDL. A mechanistic study and review of volatile products from peroxidation of unsaturated fatty acids: an aid to understanding the origins of volatile organic compounds from the human body. J Breath Res. 2020 May;14(3):034001.
28. Rahman I, Kelly F. Biomarkers in breath condensate: a promising new non-invasive technique in free radical research. Free Radic Res. 2003 Dec;37(12):1253–66.

About Owlstone Medical Ltd

Owlstone Medical is developing a breathalyzer with a focus on non-invasive diagnostics for cancer, inflammatory disease and infectious disease, the company aims to save 100,000 lives and $1.5B in healthcare costs.

The company’s Breath Biopsy^® platform has introduced a new diagnostic modality making it possible to discover novel non-invasive biomarkers in breath using a platform with the potential to transition to point-of-care. The award winning ReCIVA Breath Sampler ensures reliable collection of breath samples.

Breath Biopsy is supporting research into early detection and precision medicine with applications in cancer and a wide range of other medical conditions. Highly sensitive and selective, these tests allow for early diagnosis when treatments are more effective and more lives can be saved.

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