Parametric response map registered CT feature and small airway physiology analysis in asthma

Asthma is a disease characterized by spatiotemporal ventilation heterogeneity (VH). We hypothesized that imaging biomarkers of VH, extracted from parametric response map (PRM) registered inspiratory and expiratory CT scans in asthma, would be associated with asthma severity and small airway physiology. We aimed to evaluate PRM based CT features including a novel spatially regionalized approach, stratified axial analysis (SAA), in a cohort of asthma patients and healthy volunteers. We hypothesized that SAA biomarkers would associate with VH small airway biomarkers Sacin and R5-R20. 41 patients with asthma and 11 healthy age-matched volunteers underwent inspiratory (expiratory) volumetric CT scanning at TLC (FRC). CT biomarkers, notably SAA based inferior-superior ventilation slope (SAAz), were calculated. Linear discriminant analysis (LDA) was utilized to understand how spirometry, clinical and CT feature sets could discriminate Sacin and R5-R20. SAAz was found to provide the best single feature discriminator for both Sacin and R5-R20. LDA demonstrated that CT based feature sets can contribute significantly to VH discrimination. Polar analysis of SAAz revealed statistically significant (p < 0.05) ventilation gradient reversal [Figure 1]. We developed a novel stratified axial based CT imaging biomarker of inferior-superior ventilation gradient in asthma, which associates with small airway biomarkers of VH

Functional Ct Imaging For Identification Of The Spatial Determinants Of Small Airways Disease In Adult Asthma.

BACKGROUND: Asthma is a disease characterised by ventilation heterogeneity (VH). A number of studies have demonstrated that VH markers derived using impulse oscillometry (IOS) or multiple breath washout (MBW) are associated with key asthma patient related outcome measures and airways hyper responsiveness. However the topographical mechanisms of VH in the lung remain poorly understood. OBJECTIVES: We hypothesised that specific regionalisation of topographical small airway disease would best account for IOS and MBW measured indices in patients. METHODS: We evaluated paired expiratory/inspiratory computed tomography in a cohort of asthmatic (n=41) and healthy volunteers (n=11) to understand the determinants of clinical VH indices commonly reported using IOS and MBW. Parametric response mapping (PRM) was utilised to calculate functional small airways disease marker PRMfSAD and Hounsfield unit (HU) based density change from total lung capacity to functional residual capacity (ΔHU); gradients of ΔHU, in gravitationally perpendicular (parallel), inferior-superior (anterior-posterior) axes, were quantified. RESULTS: ΔHU gradient in the inferior-superior axis provided the highest level of discrimination of both Sacin and R5-20. Patients with a high inferior-superior ΔHU gradient demonstrated evidence of reduced specific ventilation in the lower lobes of the lungs and high levels of PRMfSAD. A computational small airway tree model confirmed that constriction of gravitationally dependant lower zone small airway branches would promote the largest increases in R5-R20. Ventilation gradients correlated with asthma control and quality of life but not with exacerbation frequency. CONCLUSIONS: Lower lobe predominant small airways disease is a major driver of clinically measured VH in adult asthma

Phenotypic and functional translation of IL33 genetics in asthma.

BACKGROUND:Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. Interleukin 33 (IL33) single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum, and bronchial biopsies of asthma patients. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE:We studied whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. We investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS:Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG/GASP cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modelling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS:161 SNPs spanning the IL33 region associated with one or more asthma phenotypes after correction for multiple testing. We report one main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/FVC, atopy, and age of asthma onset. The two IL33 signals are expression quantitative loci (eQTLs) in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and ROS-capturing of HBECs, without influencing epithelial cell count, metabolic activity or barrier function. CONCLUSION:We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma