Breath biomarkers offer a route to more effective personalized treatments
An estimated 339 million people worldwide have asthma1, but a lack of stratifying diagnostics means that current guidelines advocate a ‘trial and error’ approach, which results in increased healthcare costs, prolonged periods of poor disease control, and an increased risk of exacerbations.
Asthma management is focused on achieving control of symptoms to minimize the risk of future exacerbations. Many patients do not respond sufficiently to treatment, however, so their symptoms are not kept adequately under control. In the UK, 4.4% of patients fail to respond to standard therapies even at high doses, and account for more than half of asthma costs to the NHS. Similarly, in the US, the estimated annual economic cost of asthma, including missed work days, is $81.9 including 9.8 million doctor’s appointments and 1.8 million emergency department visits2.
Breath analysis offers the possibility of a rapid, straightforward and non-invasive method to stratify patients into receiving the right therapy and monitor what dosage they need3. While early studies in this area primarily focused simply on asthma diagnosis, a growing number of results are now highlighting the potential to use breath analysis to monitor treatment response and symptom control.
Precision Medicine for Asthma
The treatment of asthma can be challenging because the condition consists of a number of complex, overlapping, phenotypes (Figure 1, top row) with similar symptoms, but which require different treatments.
Chronic airway inflammation has diverse origins and triggers, and can be broken down into a range of different subtypes of pulmonary inflammation. These inflammatory subtypes (Figure 1, second row) can be further divided into different endotypes, with different underlying molecular mechanisms or responses to treatment.
There is now a considerable move towards precision medicine in asthma, as highlighted by Dr Stephen Fowler at the 2018 Breath Biopsy Conference and in the Lancet Respiratory Asthma Task Force and others4,5. By identifying different disease endotypes or treatable traits, precision medicine addresses asthma’s underlying heterogeneity, enabling the right treatment to be given to the right patient at the right time.
Recent years have seen the approval of biological drugs such as XOLAIR®, NUCALA®, CINQAIR®, FASENRA®, and DUPIXENT® targeted at specific pathways relevant to inflammatory subtypes, yet their approval for clinical use has been delayed due to the high cost of the treatment, combined with the difficulty of identifying patients with the correct asthma phenotype who would benefit from the drug. An increasing body of evidence shows that volatile metabolites in exhaled breath are promising biomarkers that relate to metabolic changes caused by inflammation of the airways . The existing research examining VOCs in adult asthma has been recently reviewed6,7. To date, around 20 relevant projects have been completed using data from over 1400 subjects. Despite the limitations of these studies, there is a growing body of evidence for the utilisation of breath VOCs in a number of asthma applications.
One existing breath-based biomarker, fractional exhaled nitric oxide (FENO), is already being used to support asthma diagnosis. FENO reflects a protective biochemical pathway of the lungs, but lacks specificity, as it is a single biomarker affected by many processes other than asthma. By comparison, the ability to analyse many VOCs simultaneously provides a much richer dataset with the potential to both diagnose and stratify conditions based on metabolic characteristics.
Breath Biopsy® enables you to analyze volatile metabolites in exhaled breath, providing a new non-invasive approach to characterize different disease endotypes.
Breath Biopsy® for asthma diagnosis and stratification
Studies have demonstrated that volatile organic compounds (VOCs) in exhaled breath can outperform FENO and lung function tests as biomarkers when discriminating between asthmatics and healthy controls9.
Discrimination of Asthmatic vs. Non-Asthmatic Patients with Breath Biopsy®
We’ve examined the ability of VOCs analyzed using our Breath Biopsy platform to discriminate between asthmatic and non-asthmatic patients (Figure 2). As you can see, even in a heterogeneous clinical trial population, which included individuals with a wide variety of pulmonary conditions, the VOC profile discriminates well between patients with and without an asthma diagnosis.
Distinguishing Inflammatory Subtypes in Asthma
There is compelling evidence that breath VOCs can be used to classify patients by asthma phenotype with high accuracy. Schleich et al.3 have presented the most robust study of VOC biomarkers for asthma stratification to date. The study demonstrates that the capacity for VOCs to identify eosinophilic asthma is comparable to results using serum eosinophil counts or FENO (AUC 0.72, 0.71 and 0.70 respectively). Furthermore, they showed that combining approaches produces even clearer results (AUC 0.87).
In addition to being able to reliably distinguish eosinophilic, neutrophilic and paucigranulocytic asthma phenotypes, this study is also notable for its size and use of independent validation datasets. These features provide a strong example for future studies by adhering to the international Standards for Reporting of Diagnostic Accuracy (STARD) guidance, and demonstrating robustness to the use of different analytical approaches.
Other studies, such as Ibrahim et al.12, have also provided evidence that VOCs in breath correlate with different inflammatory subtypes in asthma. VOC biomarkers in breath therefore have the clear potential to enable asthma cases to be stratified on the basis of inflammatory responses.
Breath Biopsy for Distinguishing Controlled vs. Uncontrolled Asthma
Reliable biomarkers to identify patients with uncontrolled asthma, or to predict exacerbations, would inform treatment decisions and facilitate disease management.
The profile of VOCs in exhaled breath can be used to distinguish between patients with controlled and uncontrolled asthma (Figure 3), which is an important aspect of a patient’s asthma phenotype. A study is also planned to investigate the potential of Breath Biopsy to detect VOCs associated with acute breathlessness, a feature of asthma and COPD exacerbations.
It has also been reported that breath VOCs analysed using our FAIMS technology can potentially predict loss of control in asthma11. In this study the Lonestar VOC Analyzer, was shown to outperform sensor array type eNoses and gas chromatography-mass spectrometry (GC-MS).
VOCs for Treatment Stratification
A reliable tool to identify whether a patient is likely to respond to a particular treatment would be an important development in effective asthma treatment.
Predicting Steroid Responsiveness
Van der Schee et al. that found that VOCs in breath are able to predict responsiveness to steroid treatment in steroid-naïve, mild to moderate asthma patients12. With an area under the curve of 0.88, VOCs outperformed both FENO and measurements of eosinophil cells from sputum samples.
The ability to monitor how a patient’s body responds to treatment can be used to help optimise treatment doses for an individual’s unique metabolism (learn more - EVOC® Probes). Treatment monitoring can also be used to ensure patients are adhering to treatment regimes. Additionally, bronchodilators are also used as performance enhancers in competitive sports, so breath tests for asthma drugs could also be applied in drug testing for athletes. Currently, urine analysis is the most widely used approach to monitor drug excretion from the body for these purposes.
A 2019 study13 compared the potential of using VOCs to detect drug pharmacokinetics to the use of urine testing for two drugs, salbutamol and oral corticosteroids (OCS). The resulting models respectively used seven and four VOCs to discriminate treated from untreated patients. There was no overlap between VOCs in the two models, which achieved AUROCs of 0.82 and 0.79 respectively. Although this study is small (78 subjects, 108 breath samples) it is notable for its extensive validation of results.
Breath VOCs Differentiate Treatment Groups
Promising initial results from the U-BIOPRED (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes) consortium project show that VOCs measured using a Lonestar VOC Analyzer could be used to stratify asthmatic patients into treatment subgroups. For example, VOCs discriminated between anti-IgE-treated XOLAIR and non-treated severe asthma patients with 83% accuracy14,15.
- The Global Asthma Report, The Global Asthma Network (2018). http://www.globalasthmareport.org/index.html
- Asthma and Allergy Foundation of America - Asthma Facts https://www.aafa.org/asthma-facts/
- Schleich et al., Exhaled Volatile Organic Compounds are Able to Discriminate between Neutrophilic and Eosinophilic Asthma, Am J Respir Crit Care Med, (2019). doi.org/10.1164/rccm.201811-2210OC
- Pavord et al., After asthma: redefining airways diseases, The Lancet, (2017). dx.doi.org/10.1016/S0140-6736(17)30879-6
- Chung, Personalised medicine in asthma: time for action, Eur. Resp. Rev., 26, (2017). dx.doi.org/10.1183/16000617.0064-2017
- Azim et al., Exhaled volatile organic compounds in adult asthma: a systematic review, Eur. Resp. J., 54 (2019). dx.doi.org/10.1183/13993003.00056-2019
- Brinkman et al. Exhaled volatile organic compounds as markers for medication use in asthma, Eur. Resp. J. 54 (2019). dx.doi.org/10.1183/13993003.00544-2019
- Reinke et al., Metabolomics analysis identifies different metabotypes of asthma severity, Eur. Resp. J., 49, (2017). dx.doi.org/10.1183/13993003.01740-2016
- Pité et al., Metabolomics in asthma: where do we stand?, Curr. Opin. Pulm. Med. (2017). dx.doi.org/10.1097/MCP.0000000000000437
- Ibrahim et al., Non-invasive phenotyping using exhaled volatile organic compounds in asthma., Thorax, 66 (2011) 804–809. dx.doi.org/10.1136/thx.2010.156695
- Montuschi et al., Diagnostic performance of an electronic nose, fractional exhaled nitric oxide, and lung function testing in asthma, Chest. 137 (2010) 790–796. dx.doi.org/10.1378/chest.09-1836
- van der Schee et al., Predicting steroid responsiveness in patients with asthma using exhaled breath profiling, Clin. Exp. Allergy. 43 (2013) 1217–1225. dx.doi.org/10.1111/cea.12147
- Brinkman et al., Exhaled volatie organic compounds as markers for medication use in asthma. Eur. Respir. J. (2019) 54 (4) doi.org/10.1183/13993003.00544-2019
- Santini et al., Discrimination between oral corticosteroid-treated and oral corticosteroid-non-treated severe asthma patients by an electronic nose platform, Eur. Respir. J. 44 (2014). erj.ersjournals.com/content/44/Suppl_58/P2054
- Santini et al., Breathomics can discriminate between anti IgE-treated and non-treated severe asthma adults, Eur. Respir. J. 46 (2015). http://erj.ersjournals.com/content/46/suppl_59/OA1463
- Dallinga et al., Volatile organic compounds in exhaled breath as a diagnostic tool for asthma in children, Clin. Exp. Allergy., 40 (2010). 68-76 40:1 68-76 doi.org/10.1111/j.1365-2222.2009.03343.x
- Smolinska 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). doi.org/10.1371/journal.pone.0095668
- Neerincx et al., Breathomics from exhaled volatile organic compounds in pediatric asthma, Pediatric Pul. 52 (12) 1616-1627. (2017). doi.org/10.1002/ppul.23785
ReCIVA® Breath Sampler
Reliable and reproducible, non-invasive Breath Biopsy® sample collection
Lonestar VOC Analyzer
An easy to use analyzer for the detection of VOC biomarkers in clinical samples