An Integrated Analysis of Fluticasone Furoate/Vilanterol (FF/VI) Versus FF Safety Data Across Phase II and III Asthma Studies

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s41030-016-0015-1?view=classic">https://link.springer.com/article/10.1007/s41030-016-0015-1?view=classic</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

Are There Neurophenotypes for Asthma? Functional Brain Imaging of the Interaction between Emotion and Inflammation in Asthma

<div><h3>Background</h3><p>Asthma is a chronic inflammatory disease noteworthy for its vulnerability to stress and emotion-induced symptom intensification. The fact that psychological stress and mood and anxiety disorders appear to increase expression of asthma symptoms suggests that neural signaling between the brain and lung at least partially modulates the inflammatory response and lung function. However, the precise nature of the neural pathways implicated in modulating asthma symptoms is unknown. Moreover, the extent to which variations in neural signaling predict different phenotypes of disease expression has not been studied.</p> <h3>Methods and Results</h3><p>We used functional magnetic resonance imaging to measure neural signals in response to asthma-specific emotional cues, following allergen exposure, in asthmatics with a dual response to allergen challenge (significant inflammation), asthmatics with only an immediate response (minimal inflammation), and healthy controls. The anterior insular cortex was differentially activated by asthma-relevant cues, compared to general negative cues, during the development of the late phase of the dual response in asthmatics. Moreover, the degree of this differential activation predicted changes in airway inflammation.</p> <h3>Conclusions</h3><p>These findings indicate that neurophenotypes for asthma may be identifiable by neural reactivity of brain circuits known to be involved in processing emotional information. Those with greater activation in the anterior insula, in response to asthma-relevant psychological stimuli, exhibit greater inflammatory signals in the lung and increased severity of disease and may reflect a subset of asthmatics most vulnerable to the development of psychopathology. This approach offers an entirely new target for potential therapeutic intervention in asthma.</p> </div

Experimental Design.

<p>Timing of experimental challenges and measures collected. Participants underwent both Ag and Meth challenges separated by at least 4 wk, in a complete within-subjects crossover design. Challenge order was counterbalanced and double-blind.</p

Overlap in voxels in the right anterior insula between the cluster showing a group x challenge x valence interaction and the cluster showing a correlation with increase in sputum eosinophils during Ag challenge.

<p>Red voxels indicate the area of overlap; blue voxels belong to only the cluster showing a 3-way interaction; green voxels belong to only the cluster showing the correlation with eosinophils.</p

Greater percentage of sputum EOS during Ag challenge in late-phase responders.

<p>Percentage of sputum eosinophils 24 h post-challenge relative to pre-challenge (group x challenge interaction; <i>F</i>(2,24) = 8.16, <i>p</i> = .002). The increase in EOS for the LPR group was greater than that of both the NLPR (<i>t</i>(15) = 2·13, <i>p</i> = .05) and controls (<i>t</i>(17) = 4.95, <i>p</i><.001) following the Ag challenge. The NLPR group showed a small, but significantly greater increase in EOS than controls (NLPR vs. Control: <i>t</i>(16) = 2.64, <i>p</i> = .018). No group differences were present following the Meth challenge (LPR vs. NLPR: <i>t</i>(15) = −1.38, <i>p</i> = .19; LPR vs. Control: <i>t</i>(17) = −1.07, <i>p</i> = .30; NLPR vs. Control: <i>t</i>(16) = 1.16, <i>p</i> = .26). Error bars represent standard error of the mean.</p

Individuals with asthma who have a late phase response show increased anterior insular reactivity to asthma-related words, during an antigen challenge relative to a methacholine challenge, compared to their response to negative or neutral words.

<p>The difference in right anterior insula response to asthma-related versus negative words, during antigen versus methacholine challenge (Ag(As-Ng)-Meth(As-Ng)) in the late phase group was significantly different from the insula response of both the non-late phase group (F(1,15) = 6.47, <i>p</i> = .02) and the control group (F(1,17) = 10.53, <i>p</i> = .005). (To see % signal change in the insula during individual conditions, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040921#pone.0040921.s001" target="_blank">Figure S1</a>). The overall group x challenge x valence interaction was significant (F(4, 48) = 3.24, <i>p</i><.05). Error bars represent standard error of the mean. Coordinates are in Montreal Neurological Institute Space (MNI).</p

Insula activity predicts magnitude of airway obstruction and cognitive interference of disease-related information during the late phase response to Ag.

<p>Percent signal change in the right mid- and posterior insula in response to asthma compared to negative words [As-Ng] and (a) percent peak fall in FEV₁ [Ag-Meth] (<i>r</i> = −.59, <i>p</i> = .001) and (b) reaction time to identify the color of As words, relative to Ng words [Ag(As-Ng)-Meth(As-Ng)] (<i>r</i> = .66, <i>p</i><.001) during late phase antigen relative to methacholine challenge. Coordinates are in MNI space.</p

Insula activity predicts peripheral measures of inflammatory potential.

<p>Percent signal change in the (a) anterior (<i>r</i> = .73, <i>p</i><.001) and (b) posterior (<i>r</i> = .56, <i>p</i> = .003) insula in response to asthma, compared to negative words, during antigen, relative to methacholine challenge (Ag[As-Ng]-Meth[As-Ng]) and percentage of EOS in sputum during late phase antigen relative to methacholine challenge [Ag-Meth]. Coordinates are in MNI space.</p

Group x time x valence interaction in reaction time to identify the color of the word stimulus (F(2,14) = 4.46, <i>p</i> = .032) among individuals with asthma.

<p>The only pair-wise comparison to reach a significance level of <i>p</i><.05 is the difference between the response of the NLPR group to Ng words between Ag and Meth challenge (t(7) = −2.61, <i>p</i> = .035).</p

Expression of asthma susceptibility genes in bronchial epithelial cells and bronchial alveolar lavage in the Severe Asthma Research Program (SARP) cohort

<p><i>Objective</i>: Genome-wide association studies (GWASs) have identified genes associated with asthma, however expression of these genes in asthma-relevant tissues has not been studied. This study tested expression and correlation between GWAS-identified asthma genes and asthma or asthma severity. <i>Methods</i>: Correlation analyses of expression levels of GWAS-identified asthma genes and asthma-related biomarkers were performed in cells from human bronchial epithelial biopsy (BEC, <i>n</i> = 107) and bronchial alveolar lavage (BAL, <i>n</i> = 94). <i>Results</i>: Expression levels of asthma genes between BEC and BAL and with asthma or asthma severity were weakly correlated. The expression levels of <i>IL18R1</i> were consistently higher in asthma than controls or in severe asthma than mild/moderate asthma in BEC and BAL (<i>p</i> < 0.05). In <i>RAD50-IL13</i> region, the expression levels of <i>RAD50</i>, not <i>IL4, IL5</i>, or <i>IL13</i>, were positively correlated between BEC and BAL (ρ = 0.53, <i>P</i> = 4.5 × 10⁻⁶). The expression levels of <i>IL13</i> were positively correlated with <i>IL5</i> in BEC (ρ = 0.35, <i>P</i> = 1.9 × 10⁻⁴) and <i>IL4</i> in BAL (ρ = 0.42, <i>P</i> = 2.5 × 10⁻⁵), respectively. rs3798134 in <i>RAD50</i>, a GWAS-identified SNP, was correlated with <i>IL13</i> expression and the expression levels of <i>IL13</i> were correlated with asthma (<i>P</i> = 0.03). rs17772583 in <i>RAD50</i> was significantly correlated with <i>RAD50</i> expression in BAL and BEC (<i>P</i> = 7.4 × 10⁻⁷ and 0.04) but was not associated with asthma. <i>Conclusions</i>: This is the first report studying the expression of GWAS-identified asthma genes in BEC and BAL. <i>IL13</i>, rather than <i>RAD50, IL4</i>, or <i>IL5</i>, is more likely to be the asthma susceptibility gene. Our study illustrates tissue-specific expression of asthma-related genes. Therefore, whenever possible, disease-relevant tissues should be used for transcription analysis.</p