Functional location of airway inflammation in eosinophilic asthma

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.

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.