Small Airways Disease Parameters Defined By PExA Particle Mass In Asthma, Asthma Remission And Healthy Controls
Epidemiology, diagnosis and monitoringIntroduction: asthma is a chronic pulmonary disease, characterized by variable airflow obstruction, airway inflammation, with subsequent damage and dysfunction of the small airways. Small airways are defined as airway generations become smaller than 2mm, starting from the terminal bronchioles and ending in the alveolar sacs. They are thought to be the major site of pathology in asthma, yet there are difficult to study and target. There are different tools to assess small airways dysfunction (SAD), e.g. spirometry, plethysmography, impulse oscillometry (IOS), multiple breath nitrogen wash-out (MBNW), fractional nitric oxide (FENO) and high resolution CT (HRCT). But some of these techniques are either unspecific to small airways changes or difficult to perform by the patient. PExA (Particles of Exhaled Air) is a method that counts mass of the suspended particles of the respiratory tract lining fluid from the small airways. The reduction in the particles may be due to inflammation in the small airways, which would reduce their diameter and could potentially block these.
Some patients with asthma outgrow their disease and reach clinical asthma remission (ClinR); these individuals experience no asthma symptoms even without using asthma medication. It is, however, debatable whether subjects with ClinR have actually outgrown their condition because they might still have (asymptomatic) bronchial hyperresponsiveness (BHR) or impaired lung function. Additionally, Broekema et al. demonstrated that subjects with ClinR still had ongoing airway inflammation (Broekema et al., AJCCRM 2011). A smaller subset of asthma remission subjects regained normal lung function and do not express bronchial hyperresponsiveness any longer, which are defined as complete asthma remission (ComR).Since the PExA measurements were able to differentiate asthmatics from healthy controls (Larsson et al., Clin Physiol Funct Imaging 2017), we hypothesized that this device might distinguish ComR and ClinR from persistent asthmatics (PersA) as well.
Aim: We hypothesize that healthy subjects exhale more particle mass than asthma or asthma remission subjects, and that PExA is a method that closely relates to established small airways parameters.
Methods: subjects aged 40-65 years, never-smokers or past-smokers with a smoking history of <10 pack years, were enrolled in four groups; persistent asthmatics (PersA; persisting symptoms and asthma-medication use since childhood, with a positive PC20 methacholine test), clinical asthma remission (ClinR; no wheeze or asthma attacks, no asthma-medication use, documented history of childhood-onset asthma according to GINA guidelines, with an FEV1 % predicted <80% or PC20 methacholine <9.8mg/ml), complete asthma remission (ComR; similar to ClinR, but with an FEV1 % predicted ≥80%, PC20 methacholine ≥9.8mg/ml and PC20 adeno-‘5-monophosphate ≥320mg/ml) and healthy controls (Ctrl; similar to ComR, but without any history of asthma and asthma-medication). PersA-subjects stopped inhaled corticosteroids (ICS) 6 weeks prior to the visits. During these visits, subjects underwent the following tests: PExA, spirometry, plethysmography, MBNW, FEno , sputum induction and a HRCT.
Results: 16 controls, 11 ComR-, 15 ClinR- and 16 PersA were included. The median age was 55 [IQR 47 - 60]. The mean smoked pack years was 0.6 [min 0, max 6]. The amount of particle mass was 5.2ng/L [IQR 2.4 - 9.6] in Ctrl-, 4.4ng/L [IQR 2.4 - 6.0] in ComR-, 3.9ng/L [IQR 1.0 - 5.9] in ClinR-, and 2.1ng/L [IQR 0.5 - 3.7] in PersA-subjects (log2 transformed in figure 1A). PExA paticle mass was significantly lower in PersA- compared to Ctrl- and ComR-subjects (P=0.003 and P=0.025 respectively). PExA particle mass was positively correlated with FEV1% predicted, FEV/FVC ratio, FEF25-75% (figure 1B-D), and negatively correlated with RV % predicted, IOS R5-R20, sputum eosinophils, MBNW Scond, methacholine slope (figure 1E-I), and more. There was a negative trend seen in inferior to superior ventilation gradient measured by inspiration-expiration HRCT parameteric response mapping (figure 1J). (Alveolar) FEno and MBNW Sacin did not correlate with PExA particle mass.
Conclusion: healthy controls and subjects in complete asthma remissionshowed a significantly higher PExA particle mass compared to asthmatics, suggesting that clinical asthma remission still might have a degree of small airways disease. Additionally, PExA particle mass was associated with small- (i.e. FEF25-75%, IOSR5-R20, RV% predicted)and larger airways parameters (FEV1 % predicted, bronchial hyperresponviness).