Functional location of airway inflammation in eosinophilic asthma

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


Asthma is a prevalent, complex and highly heterogeneous chronic airways disease, whose treatment is guided by its classification according to levels of type 2 inflammation, namely into 'TH-2 high' and 'TH-2 low' subtypes (commonly called endotypes), with TH-2 high asthma being responsive to treatment with inhaled corticosteroids, while TH-2 low asthma is not. Despite the success of endotyping, there remains the important issue that while TH-2 high asthma is generally responsive to treatment with inhaled corticosteroids, a substantial subgroup of patients with this endotype have persistent symptoms and uncontrolled asthma despite such treatment. There may be several reasons for this failure to respond, one of which is if the location of the inflammation within the airway tree renders it inaccessible to inhaled therapy, i.e. is the inflammation in the proximal or distal airways. This proposal seeks to address this outstanding question in the treatment of TH-2 high asthma by developing a world-leading instrument capable of functionally locating airways inflammation. The instrument will combine highly time-resolved measurements of the fraction of exhaled nitric oxide, FeNO, with highly precise measurements of respiratory gas exchange to assess functional inhomogeneity in the lung, and thereby help ascertain which TH-2 patients, which constitute more than 50% of all asthmatics, are most likely to be unresponsive to inhaled steroid therapy.

A key feature of asthma is the variability of symptoms over time - between attacks patients may display apparently normal lung function and, when attacks occur, a number of treatments may be used to reverse airway inflammation. Measurement of FeNO is already a reliable NICE approved method of detecting the presence of eosinophilic airway inflammation, however current methods provide a single FeNO value from sustained expiration at constant flow. This is an important limitation as it is not possible to determine the site of NO production and hence the location of the inflammation within the airways. Furthermore, even if a time-resolved FeNO measurement were obtained, there is no recognition of the fact that the asthmatic lung is highly inhomogeneous and therefore any such time-resolved FeNO can only be interpreted in terms of the person-specific lung inhomogeneity. This research will provide a sea-change in the location and quantification of inflammation by linking for the first time, quantitative and individualised measures of lung inhomogeneity and structure with time-resolved measurements of FeNO.

Planned Impact

The proposed research will develop an instrument capable of both measuring the fraction of nitric oxide in exhaled breath, FeNO, a marker for eosinophilic airways inflammation (EAI), and interpreting this measurement on a person-specific basis, using individualised measurements of lung inhomogeneity, to locate EAI. The work directly addresses the need for better ways of assessing lung disease in type-2 asthma with a view to better management of patients with existing therapeutic options.
At the heart of the research is a recognition of the importance of inhomogeneity and its different forms. Inhomogeneities generate ventilation-perfusion mismatch within the lung and underlie much of the respiratory failure in chronic airways disease and measures of inhomogeneity therefore have the potential to be very sensitive markers of early disease and its progression. This is because organs generally consist of multiple smaller functional units and disease typically progresses by affecting some units more than others: parameters reflecting inhomogeneity across an organ respond much more quickly to early disease than those reflecting the overall level of disease. The work therefore directly addresses the core need for better ways of measuring lung disease in general, both for the development of novel therapeutics and for better management of patients with existing therapeutic options. One requirement is to be able to detect and track progression of lung damage much earlier in the overall disease process. A second requirement is for measurements that are better for stratifying patients and predicting their individual responses to a particular treatment. A third requirement is for measurements that can track response to therapy. Finally, there is a need for measurements that can help us to understand better the onset and development of exacerbations (or attacks), as these are sentinel events in asthma, and are associated with major health care expenditure.
The work that we propose, particularly the improvements for molecular flow sensing, will also be welcomed in other areas. For example, in military aviation both high-G and low-G conditions occur during fast jet operations. Currently the Royal Air Force has serious concerns about fighter pilots experiencing significant symptoms associated with hypoxia during and after flight which are thought to be related to gravitational effects on the lung that are not well understood. This proposal will also directly support the British government's stated aim of positioning the UK as the European centre of sub-orbital spaceflight, including the development of an operational UK spaceport by 2020. Commercial sub-orbital spaceflights are projected to commence before then and will present new and profound physiological challenges both for flight crew and passengers. Anticipated flight profiles include exposure to high-G forces during launch and re-entry phases that are actually more extreme than those experienced by professional astronauts on NASA's Space Shuttle, yet passengers will be members of the public with widely varying age and baseline health. In-flight hypoxia may well occur commonly as a result of unexplored effects on the lungs, and could be dangerous in some cases.


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Description In the T helper 2 (Th2)-high asthma subtype, the production of nitric oxide (NO) is greatly enhanced from the sites of inflammation, and the lung is also more inhomogeneous in terms of gas exchange. Over the past decades, researchers have improved measurements and models for the fraction of exhaled NO (FeNO), thereby leading to a better understanding of the complexities of this asthma endotype. Although Th2-high asthma is generally well-controlled with inhaled corticosteroid (ICS) treatment, a substantial subgroup of these patients are ICS non-responders. This results not only into significant healthcare costs but also in unnecessary high ICS dosage with the risk of side effects. It is crucial to non-invasively assess the location of inflammation and predict adherence to ICS therapies. To this end, we have developed a novel methodology based on combining time resolved FeNO profiles with highly precise measurements of respiratory gas exchange that assess functional inhomogeneity in the lung. For each patient we acquire multiple simultaneous FeNO and CO2 expirograms, followed by a N2 washout scan utilising our laser-based sensors. Specifically, from the gas-exchange data of each individual, our mechanistic pulmonary model evaluates the particular type and degree of inhomogeneity; FeNO production is therefore examined in the context of an inhomogeneous lung. The patient-specific lung parameters are then used to produce bespoke simulation of the CO2 and FeNO profiles with which to interpret the measured data.
Within a collaboration between the departments of Chemistry, Physiology and Genetics, and the Nuffield Department of Medicine in Oxford we are performing a pilot study in clinic to show the applicability of this novel methodology. We are in the process of collecting this type of data on asthmatic patients at the Respiratory Medicine Unit of the John Radcliffe Hospital in Oxford. These data are being validated by 3D simulations on anatomically accurate lung models and in collaboration with researchers at the University of Loughborough and which have been mediated by the BioReme network.
Exploitation Route The device that we have developed is mobile and is now currently located in a clinical setting allowing us to finally obtain unique pilot data.
Sectors Healthcare

Description Integrating Data-driven Biophysical Models Into Respiratory Medicine Postdoctoral Research Associate Awards
Amount £83,925 (GBP)
Funding ID EP/W000490/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2022 
End 09/2023
Description MRC open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Showcasing the MFS technology to the general public and showing what research advances we are making and inspiring them to participate as healthy volunteers.
Year(s) Of Engagement Activity 2022
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact One postdoctoral researcher and one graduate student presented the molecular flow sensing technology and it is use in the complex airways disease unit to an audience comprising the general public.
Year(s) Of Engagement Activity 2023
Description The ins and outs of breath analysis: using laser spectroscopy to evaluate heart and lung function 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 50 members of the public attended an online Cafe Scientifique discussion of my research into breath analysis. The talk sparked several interesting questions and discussion afterwards on a range of topics from the underlying science to health economics and lots in between. The audience were drawn from a range of backgrounds.
Year(s) Of Engagement Activity 2021