Asthma

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.

Precision Medicine for Asthma
Figure 1. Precision Medicine for Asthma. Asthma management is challenging due to multiple phenotypes, inflammatory subtypes and endotypes with different underlying molecular mechanisms or responses to treatment. Metabolomics is being explored as a route to discover biomarkers to identify disease endotypes or treatable traits, enabling a precision medicine approach to asthma treatment.

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 [60]. 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.

Discriminating between asthmatics and non-asthmatics using Breath Biopsy

Figure 2. Breath VOCs analyzed using Owlstone Medical’s Breath Biopsy platform were used to build a classifier which could discriminate between patients with or without a diagnosis of asthma. The Receiver Operator Characteristics (ROC) curve shows an area under the curve of 0.92. The ROC evaluates the ability of a test to discriminate between states with 1.0 indicating a perfect test. The patient population included individuals with a wide variety of pulmonary conditions, participating in a larger clinical trial.

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.

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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.

Distuinguishing controlled and uncontrolled asthma with Breath Biopsy

Figure 3. Breath VOCs analyzed using Owlstone Medical’s Breath Biopsy platform were used to build a classifier which could identify individuals with self-reported uncontrolled asthma with 85% sensitivity and 98% specificity. The Receiver Operator Characteristics (ROC) curve shows an area under the curve of 0.88. A subpopulation of individuals participating in a larger clinical trial were included in this analysis.

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.

Treatment Monitoring

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.

Breath Analysis for Pediatric Asthma

Using VOCs to diagnose asthma and to distinguish it from other physiologically similar conditions is of particular interest in pediatric medicine, where existing tests are typically to invasive or require complex breath maneuvers that cannot be performed by young children. For example, VOCs can be used to discriminate with a high degree of accuracy between asthmatic children and those with transient wheezing16. A study specifically focusing on pre-school children achieved 80% accuracy in discriminating these two conditions17.

A 2017 review18 identified 12 publications examining exhaled VOC biomarkers for asthma in children. Together, these proposed 111 possible biomarkers and generated reliable discriminatory models based on between 6 and 28 VOCs. Only 13 VOCs were identified in multiple studies, although this is not surprising given the wide variety of study goals, sample populations, collection and analysis techniques used. Despite the clear need for better tests in this area, a key limitation in the advancement of breath testing for pediatric asthma is the lack of existing gold standard data for comparison.

Summary 

Promising results indicate that VOCs in exhaled breath reflect specific molecular processes that underlie chronic inflammation in asthma, making them ideal biomarkers for precision medicine and treatment stratification. By enabling the non-invasive collection and analysis of (VOCs) in exhaled breath, Breath Biopsy provides a new approach to discover biomarkers that could characterize different asthma endotypes and predict the effectiveness of treatment.

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References

  1. The Global Asthma Report, The Global Asthma Network (2018). http://www.globalasthmareport.org/index.html
  2. Asthma and Allergy Foundation of America - Asthma Facts https://www.aafa.org/asthma-facts/
  3. 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
  4. Pavord et al., After asthma: redefining airways diseases, The Lancet, (2017). dx.doi.org/10.1016/S0140-6736(17)30879-6
  5. Chung, Personalised medicine in asthma: time for action,  Eur. Resp. Rev., 26, (2017).   dx.doi.org/10.1183/16000617.0064-2017
  6. 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
  7. 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
  8. Reinke et al., Metabolomics analysis identifies different metabotypes of asthma severity, Eur. Resp. J., 49, (2017). dx.doi.org/10.1183/13993003.01740-2016
  9. Pité et al., Metabolomics in asthma: where do we stand?, Curr. Opin. Pulm. Med. (2017).  dx.doi.org/10.1097/MCP.0000000000000437 
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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