Functional location of airway inflammation in eosinophilic asthma

哮喘是一种流行的、复杂的和高度异质性的慢性气道疾病，其治疗由其根据2型炎症水平的分类指导，即分为“TH-2高”和“TH-2低”亚型（通常称为内源性），其中TH-2高哮喘对吸入性皮质类固醇治疗有反应，而TH-2低哮喘则无反应。尽管内型分析取得了成功，但仍然存在一个重要问题，即虽然TH-2高哮喘通常对吸入性皮质类固醇治疗有反应，但尽管进行了这种治疗，仍有大量具有这种内型的患者亚组具有持续的症状和不受控制的哮喘。这种反应失败可能有几个原因，其中之一是如果气道树内的炎症位置使其无法进行吸入治疗，即炎症在近端或远端气道中。该提案旨在通过开发能够功能性定位气道炎症的世界领先仪器来解决治疗TH-2高哮喘中的这一突出问题。该仪器将结合联合收割机高度时间分辨的测量呼出的一氧化氮，FeNO的分数，与呼吸气体交换的高度精确的测量，以评估肺功能的不均匀性，从而帮助确定哪些TH-2患者，占所有哮喘患者的50%以上，是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-在发作之间，患者可能表现出明显正常的肺功能，并且当发作时，可以使用许多治疗来逆转气道炎症。FeNO的测量已经是一种可靠的NICE批准的检测嗜酸性气道炎症存在的方法，然而，目前的方法提供了一个单一的FeNO值，从持续呼气在恒定的流量。这是一个重要的限制，因为不可能确定NO产生的部位，因此不可能确定气道内炎症的位置。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匀的这一事实，因此任何这种时间分辨的FeNO只能根据个人特异性肺不均匀性来解释。这项研究将通过首次将肺不均匀性和结构的定量和个性化测量与FeNO的时间分辨测量相联系，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.