Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction Imran Satia, MD, Nikolaos Tsamandouras, PhD, Kimberley.

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Presentation transcript:

Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction Imran Satia, MD, Nikolaos Tsamandouras, PhD, Kimberley Holt, MPhil, Huda Badri, MD, Mark Woodhead, MD, Kayode Ogungbenro, PhD, Timothy W. Felton, PhD, Paul M. O'Byrne, MD, Stephen J. Fowler, MD, Jaclyn A. Smith, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 3, Pages 771-779.e10 (March 2017) DOI: 10.1016/j.jaci.2016.04.045 Copyright © 2016 The Authors Terms and Conditions

Fig 1 Model fit to the observed dose-response data stratified by significant categorical covariates: A, healthy volunteers versus asthmatic patients; B, male versus female subject; C, atopic vs nonatopic asthmatic patients. Average number of coughs (y-axis) is plotted against capsaicin dose (x-axis). Bars and red lines represent the observed and model-predicted number of coughs, respectively, averaged across all subjects in a specific covariate subpopulation and all inhalations at a given capsaicin dose level. The number of subjects in each subpopulation subjected to at least 1 inhalation at a given dose level are also reported inside (or above) each bar. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig 2 Model-simulated typical dose-response curves for subjects with different population characteristics. The typical (median) population values have been assumed for the model-incorporated continuous covariates. A, Atopic; NA, nonatopic. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig 3 Model fit to the observed dose-response data stratified by significant continuous covariates. Subpopulations are stratified in relation to the median population value of each covariate: A, low versus high cough frequency (in coughs per hour); B, low versus high ACQ score; C, low versus high IgE levels (in kilounits per liter). Average number of coughs (y-axis) is plotted against capsaicin dose (x-axis). Bars and red lines represent observed and model-predicted number of coughs, respectively, averaged across all subjects in a specific covariate subpopulation and all inhalations at a given capsaicin dose level. The number of subjects in each subpopulation subjected to at least 1 inhalation at a given dose level are also reported inside (or above) each bar. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig 4 Effect of model-incorporated continuous covariates on simulated dose-response curves: A, cough frequency (in coughs per hour); B, ACQ score; C, serum IgE levels (in kilounits per liter). Model-simulated dose-response curves show the influence of continuous covariates at 3 incremental values (5th, 50th, and 95th percentiles in the analyzed data set) by using an atopic asthmatic male subject as an example reference. The typical (median) population values have been assumed each time for the remaining continuous covariates. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig E1 Patient flow diagram illustrating the number of patients screened, withdrawals, and missing data. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig E2 Model fit to the observed dose-response data. The average number of coughs (y-axis) is plotted against the capsaicin dose (x-axis). Bars and the red line represent the observed and model-predicted number of coughs, respectively, averaged across all subjects and inhalations at a given capsaicin dose level. The number of subjects subjected to at least 1 inhalation at a given dose level is also reported inside (or above) each bar. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig E3 Model fit to the observed dose-response data at the individual level. Observed data (bars) and individual model predictions (red lines) of 16 representatives of the population subjects are presented. The number of coughs (y-axis) averaged across all inhalations at a given capsaicin dose level for a given subject is plotted against the capsaicin dose (x-axis). Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig E4 Investigation of the challenge termination pattern in the raw cough response data. A, Number of subjects (y-axis) performing at least 1 inhalation at a given dose level is plotted against the capsaicin dose (x-axis). B, Average number of total coughs in the challenge (y-axis) up to a given capsaicin dose (x-axis) for subjects who do or do not terminate the challenge after this specific dose. For example, the 4 subjects who dropped out after inhaling the 7.81 μmol/L dose (third marker from the left) had, on average, of 43 coughs up to this point of the challenge; the 137 subjects that did not drop out and continued to the higher dose level had, on average, only 13 coughs up to this point of the challenge. Markers highlighted with an asterisk indicate a statistically significant difference in total coughs between the dropout and nondropout groups at a given dose level. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions

Fig E5 Comparison of the traditional capsaicin challenge end points C2 (A) and C5 (B). Note the logarithmic scale (base 10) of the y-axis. Error bars show geometric means and 95% CIs. Dashed reference lines at 2000 μmol/L capsaicin represent values assigned to those subjects who did not achieve C2 or C5. Journal of Allergy and Clinical Immunology 2017 139, 771-779.e10DOI: (10.1016/j.jaci.2016.04.045) Copyright © 2016 The Authors Terms and Conditions