Functional location of airway inflammation in eosinophilic asthma

哮喘是一种常见的、复杂的、高度异质性的慢性呼吸道疾病，其治疗依据其2型炎症水平的分类，即分为TH-2高和TH-2低亚型(通常称为内型)，其中TH-2高哮喘对吸入皮质类固醇治疗有效，而TH-2低哮喘对吸入皮质类固醇治疗有效。尽管内型法取得了成功，但仍然存在一个重要的问题，即虽然TH-2高度哮喘通常对吸入皮质类固醇治疗有反应，但有相当一部分这种内型型的患者尽管接受了这种治疗，仍有持续的症状和无法控制的哮喘。这种反应失败的原因可能有几个，其中之一是如果炎症在气道树内的位置使其无法进行吸入治疗，即近端或远端呼吸道的炎症。这项建议寻求通过开发一种世界领先的能够对呼吸道炎症进行功能定位的仪器来解决TH-2高度哮喘治疗中的这一悬而未决的问题。该仪器将结合对呼出的一氧化氮分数FeNO的高时间分辨率测量和高精度的呼吸气体交换测量，以评估肺功能的不均一性，从而帮助确定占所有哮喘患者50%以上的TH-2患者最有可能对吸入类固醇治疗无反应。哮喘的一个关键特征是症状随时间的变化--发作之间患者可能表现出明显的正常肺功能，当发作发生时，可能会使用多种治疗方法来逆转呼吸道炎症。测量FeNO已经是一种可靠的、被批准的检测嗜酸性气道炎存在的方法，但目前的方法提供了恒定流量下持续呼气的单一FeNO值。这是一个重要的限制，因为无法确定NO产生的位置，因此无法确定呼吸道内炎症的位置。此外，即使获得了时间分辨的FeNO测量，也没有认识到哮喘肺是高度不均质性的事实，因此任何这种时间分辨FeNO只能根据特定人的肺不均质性来解释。这项研究将通过首次将肺不均质性和结构的定量和个性化测量与时间分辨的FeNO测量联系起来，在炎症的位置和量化方面提供巨大的变化。

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.