Using imaging as a biomarker for asthma Abhaya Trivedi, MD, Chase Hall, MD, Eric A. Hoffman, PhD, Jason C. Woods, PhD, David S. Gierada, MD, Mario Castro, MD, MPH  Journal of Allergy and Clinical Immunology  Volume 139, Issue 1, Pages 1-10 (January 2017) DOI: 10.1016/j.jaci.2016.11.009 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Chest CT for lung density. A, Three-dimensional volume rendition of the lung, lobes, and bronchial tree detected from a CT image of the fully inflated (total lung capacity) lung of a healthy subject. B, CT scan of the chest showing a similar volume rendition using the expiratory image (in this case functional residual capacity) of a patient with severe asthma. Note the areas of air trapping and pruning of the airways. Image processing was derived by using Apollo software (VIDA Diagnostics, Coralville, Iowa). Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Three-dimensional chest CT scan of the bronchial tree. The figure demonstrates labeling of the bronchial tree out to the segmental bronchi of a patient with severe asthma, enabling each segmental bronchial WT to be measured quantitatively. Image processing was derived by using Apollo software (VIDA Diagnostics, Coralville, Iowa). BronInt, Bronchus intermedius; LLB, left lower lobe bronchus; LMB, left mainstem bronchus; LUL, left upper lobe; RMB, right mainstem bronchus; RUL, right upper lobe. Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Chest CT scan showing air-trapping distribution. The figure demonstrates the concentration of regions determined to represent air trapping (voxels < −856) on the expiratory CT image of the same patient with severe asthma shown in Fig 1, B. Trapped air, which was defined as voxels within the lung field of less than −856 HU, are demonstrated by spheres proportional to the area of air trapping (volume-rendered view). Each lobe is color coded. Image processing was derived by using Apollo software (VIDA Diagnostics, Coralville, Iowa). Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 MDCT chest image matching. Parametric response mapping22 and disease probability mapping23,24 methods are demonstrated whereby inspiratory and expiratory scans are warped together, such that voxels can be assigned to categories of air trapped, normal, and emphysema/hyperinflated. A, Voxels from total lung capacity (y-axis) and functional residual capacity (x-axis) in terms of their probability of being hyperinflated versus ventilated in a plot from a patient with severe asthma, A healthy subject is shown in the insert (upper left). Green represents the normal end of the scale, yellow represents the probability of being air trapped (poorly ventilated), and red represents hyperinflation. Because the image is a probability map, the colors are shown blended. B, Quantitation of clusters of air-trapped versus normal lung tissue as a function of lung location. LLL, Left lower lobe; LUL, left upper lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe. Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 OCT images (A) and mean ± SD airway measurements (B) before bronchial thermoplasty (BT), 6 months after bronchial thermoplasty, and 2 years after bronchial thermoplasty, with the corresponding bronchial biopsy specimen at 6 months after bronchial thermoplasty (C). BM, Basement membrane; Epi, epithelium; SM, smooth muscle; WA, airway wall. Scale bars = 1 mm. Reproduced with permission of the European Respiratory Society from Kirby et al.35 Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 EBUS of the bronchial wall from an equine asthma model (A) and corresponding histologic (B) images. Only a portion of the second-layer (L2) area and corresponding smooth muscle area have been encircled in yellow to allow the reader to appreciate the rest of the image. D1 and D2, Perpendicular diameters (blue dotted lines); LA, lumen area (filled light green area); L1-5, ultrasound layers 1 to 5; Pi, airway perimeter (continuous green line). Modified from Bullone et al.38 © 2015 Bullone et al. Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Lung MRI demonstrates ventilation maps based on the distribution of hyperpolarized Xe gas assessed by using magnetic resonance images of a healthy subject (A) and an asthmatic patient (B), respectively. Note the patchy regions of poor to no ventilation in patients with severe asthma. Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 ADC map of a healthy nonsmoker (A), a patient with Global Initiative for Chronic Obstructive Lung Disease stage 2 chronic obstructive pulmonary disease (COPD; B), and a patient with severe asthma (C). The color scale on the right represents diffusion coefficients in square centimeters per second, with blue representing low ADC values and yellow representing higher ADC values. Notice the regions of higher ADC values in the patient with COPD corresponding to areas of alveolar destruction. Image courtesy of James Quirk, PhD, Washington University in St Louis. Journal of Allergy and Clinical Immunology 2017 139, 1-10DOI: (10.1016/j.jaci.2016.11.009) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions