129 results on '"Ana R. Sousa"'
Search Results
2. Patient‐Reported Outcome Measures for Severe Recurrent Bilateral Nasal Polyps: Psychometric Evaluation and Content Validity
- Author
-
Adam Gater, Chloe Tolley, Rebecca Williams‐Hall, Claire Trennery, Helena Bradley, Mirko V. Sikirica, Linda Nelsen, Ana R. Sousa, Daniel J. Bratton, Robert Chan, and Robyn vonMaltzahn
- Subjects
chronic rhinosinusitis ,disease severity ,quality of life ,visual analogue scale ,Otorhinolaryngology ,RF1-547 ,Surgery ,RD1-811 - Abstract
Abstract Objective To date, no patient‐reported outcome measures have been specifically developed to assess pharmacological treatment effect in participants with severe chronic rhinosinusitis (CRS) with recurrent bilateral nasal polyps (NP). These studies aimed to assess (1) the psychometric properties and (2) content validity of Visual Analogue Scales (VAS) assessing NP symptom severity. Study Design (1) Retrospective psychometric validation study using clinical trial data and (2) cross‐sectional qualitative patient interview study. Setting (1) Multicentre trial; (2) real‐world. Methods (1) Psychometric validation was performed using data from a randomized, double‐blind, placebo‐controlled, Phase II study (NCT01362244) investigating the effect of mepolizumab in 105 participants with severe, recurrent bilateral NP currently needing polypectomy surgery. (2) Content validity was explored through cognitive debriefing interviews in 27 adults with severe CRS with recurrent bilateral NP who had received NP surgery in the past 10 years (NCT03221192). Results (1) Acceptable reliability, validity, and responsiveness were shown for individual VAS items, although the loss of smell VAS item performed poorly in several analyses, suggesting further evaluation of this item is needed. (2) All individual VAS items were well understood, considered relevant and were consistently interpreted by most participants, providing evidence for their content validity. Conclusion These findings support the use of symptom VAS measures to evaluate disease experience and treatment effect in clinical trials of participants with severe CRS with recurrent bilateral NP.
- Published
- 2023
- Full Text
- View/download PDF
3. Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids
- Author
-
Valentyna Yasinska, Cristina Gómez, Johan Kolmert, Magnus Ericsson, Anton Pohanka, Anna James, Lars I. Andersson, Maria Sparreman-Mikus, Ana R. Sousa, John H. Riley, Stewart Bates, Per S. Bakke, Nazanin Zounemat Kermani, Massimo Caruso, Pascal Chanez, Stephen J. Fowler, Thomas Geiser, Peter H. Howarth, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Annelie Behndig, Dominick E. Shaw, Richard G. Knowles, Barbro Dahlén, Anke-Hilse Maitland-van der Zee, Peter J. Sterk, Ratko Djukanovic, Ian M. Adcock, Kian Fan Chung, Craig E. Wheelock, Sven-Erik Dahlén, Eva Wikström Jonsson, and H. Ahmed
- Subjects
Medicine - Abstract
Rationale Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure. Methods Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study. Measurements and main results The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were
- Published
- 2023
- Full Text
- View/download PDF
4. Mepolizumab improvements in health-related quality of life and disease symptoms in a patient population with very severe chronic rhinosinusitis with nasal polyps: psychometric and efficacy analyses from the SYNAPSE study
- Author
-
Wytske Fokkens, Andrew Trigg, Stella E. Lee, Robert H. Chan, Zuzana Diamant, Claire Hopkins, Peter Howarth, Valerie Lund, Bhabita Mayer, Ana R. Sousa, Steve Yancey, Maggie Tabberer, and SYNAPSE study group
- Subjects
SNOT-22 ,VAS ,Chronic rhinosinusitis with nasal polyps ,Psychometric ,Efficacy ,Quality of life ,Public aspects of medicine ,RA1-1270 - Abstract
Plain English summary Patients with chronic rhinosinusitis (CRS) often have blocked or runny noses, and loss of sense of smell. They can also have sac-like growths in their nose called nasal polyps, which often require surgical removement. The symptoms of CRS with nasal polyps can affect quality of life. In a clinical study named SYNAPSE, a new treatment option called mepolizumab reduced the size and severity of nasal polyps in patients suffering from very severe CRS with nasal polyps, compared with placebo. Mepolizumab also reduced the need for nasal polyp surgery. The SYNAPSE study also measured if 1 year of mepolizumab treatment improved patients’ symptoms and quality of life. This was evaluated by asking patients to complete two separate tasks. These tasks were rating symptoms on a visual analogue scale (VAS) and completing a quality of life questionnaire called SNOT-22. The objective of this analysis was to see if these questionnaires accurately assessed a patient’s quality of life. The analysis also assessed how many patients had major improvements in their symptoms with mepolizumab. Overall, data from 407 patients in the SYNAPSE study was analyzed. Results showed that both the VAS and SNOT-22 questionnaires accurately captured CRS symptoms and quality of life. In addition, patients treated with mepolizumab for 1 year had improvements in quality of life compared with placebo. In conclusion, these findings suggest that the VAS and SNOT-22 questionnaires are appropriate evaluation tools for patients with very severe CRS with nasal polyps. The findings also show that mepolizumab treatment is beneficial for these patients.
- Published
- 2023
- Full Text
- View/download PDF
5. Multifunctional Nanoparticles with Superparamagnetic Mn(II) Ferrite and Luminescent Gold Nanoclusters for Multimodal Imaging
- Author
-
Bárbara Casteleiro, Mariana Rocha, Ana R. Sousa, André M. Pereira, José M. G. Martinho, Clara Pereira, and José P. S. Farinha
- Subjects
gold nanoclusters ,manganese ferrite nanoparticles ,mesoporous silica ,multimodal imaging ,NIR-photoluminescence ,superparamagnetism ,Organic chemistry ,QD241-441 - Abstract
Gold nanoclusters (AuNCs) with fluorescence in the Near Infrared (NIR) by both one- and two-photon electronic excitation were incorporated in mesoporous silica nanoparticles (MSNs) using a novel one-pot synthesis procedure where the condensation polymerization of alkoxysilane monomers in the presence of the AuNCs and a surfactant produced hybrid MSNs of 49 nm diameter. This method was further developed to prepare 30 nm diameter nanocomposite particles with simultaneous NIR fluorescence and superparamagnetic properties, with a core composed of superparamagnetic manganese (II) ferrite nanoparticles (MnFe2O4) coated with a thin silica layer, and a shell of mesoporous silica decorated with AuNCs. The nanocomposite particles feature NIR-photoluminescence with 0.6% quantum yield and large Stokes shift (290 nm), and superparamagnetic response at 300 K, with a saturation magnetization of 13.4 emu g−1. The conjugation of NIR photoluminescence and superparamagnetic properties in the biocompatible nanocomposite has high potential for application in multimodal bioimaging.
- Published
- 2023
- Full Text
- View/download PDF
6. Extracorporeal Membrane Oxygenation in an Adolescent with Multisystem Inflammatory Syndrome in Children
- Author
-
Cristina Gago, Cristina Lorenzo, Sara Pinto, Ana R. Sousa, Cristina Camilo, and Francisco Abecasis
- Subjects
Adolescent ,COVID-19/complications ,Extracorporeal Membrane Oxygenation ,SARS-CoV-2 ,Shock, Cardiogenic ,Systemic Inflammatory Response Syndrome ,Medicine ,Medicine (General) ,R5-920 - Abstract
Multisystem inflammatory syndrome in children is a rare and potentially life-threatening disease that is associated with SARS-CoV-2 infection, characterized by hyperinflammation and multiorgan involvement. Cardiovascular involvement is common, including myocardial dysfunction often leading to cardiogenic shock. We present the case of a 17-year-old boy with fever, odynophagia, maculopapular rash and abdominal pain who developed a cardiogenic shock. Due to progressive deterioration of cardiac function despite optimized vasoactive support, veno-arterial extracorporeal membrane oxygenation support was initiated 12 hours after admission, with successful decannulation after seven days and discharge after 23 days, with normal cardiac function. The patient received corticosteroids and intravenous immunoglobulin. Early recognition and intensive care support are crucial for ensuring a successful outcome in severe cases of multisystem inflammatory syndrome. In cases of severe cardiogenic shock, extracorporeal membrane oxygenation support can be critical for survival and rapid recovery.
- Published
- 2023
- Full Text
- View/download PDF
7. Elucidating the Real-World Burden of Chronic Rhinosinusitis With Nasal Polyps in Patients in the USA
- Author
-
Victoria S. Benson PhD, Guillaume Germain MSc, Robert H. Chan MD, Ana R. Sousa PhD, Shibing Yang PhD, Jared Silver MD, PhD, Mei Sheng Duh ScD, François Laliberté MA, Rose Chang ScD, and Joseph K. Han MD
- Subjects
Otorhinolaryngology ,RF1-547 ,Surgery ,RD1-811 - Abstract
Objective To characterize healthcare burden, treatment patterns, and clinical characteristics associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Study Design Retrospective cohort. Setting Real-world study using US health insurance claims database. Methods Adults with ≥1 CRSwNP diagnosis (index date: first claim for nasal polyps [NPs] between January 1, 2008, and March 31, 2019) and continuous health insurance coverage for ≥180 days preindex (baseline) and postindex were included. Follow-up spanned from index to the earliest of disenrollment, death, or data end. Assessments included patient demographics, comorbidities, and blood eosinophil count at baseline, healthcare resource utilization (HCRU), and costs during follow-up in the overall population and stratified by number of surgeries. Results Of the 119,357 patients who met the inclusion criteria, 33,748 (28%) had ≥1 surgery during follow-up, among whom 3262 (9.7%) had ≥2 surgeries. At baseline, patients with ≥1 vs no NP surgeries had a greater comorbidity burden; a higher proportion of patients had comorbid asthma (37.8% vs 21.8%) and blood eosinophil count ≥300 cells/µL (42.6% vs 38.1%). During follow-up, patients with NP surgeries had higher all-cause and CRSwNP-related HCRU and costs than patients without NP surgery. All-cause healthcare costs per person per year increased with the number of surgeries during follow-up (no surgery, $10,628; ≥1 surgery, $20,747; ≥2 surgeries, $26,969). Conclusion Patients with CRSwNP and surgery had a greater disease burden than those without surgery, with higher HCRU and costs, and were more likely to have comorbid conditions (most commonly asthma) and elevated blood eosinophil count, indicating a subset of patients with recalcitrant CRSwNP.
- Published
- 2022
- Full Text
- View/download PDF
8. Clinical and transcriptomic features of persistent exacerbation‐prone severe asthma in U‐BIOPRED cohort
- Author
-
Uruj Hoda, Stelios Pavlidis, Aruna T. Bansal, Kentaro Takahashi, Sile Hu, Francois Ng Kee Kwong, Christos Rossios, Kai Sun, Pankaj Bhavsar, Matthew Loza, Frederic Baribaud, Pascal Chanez, Stephen J. Fowler, Ildiko Horvath, Paolo Montuschi, Florian Singer, Jacek Musial, Barbro Dahlen, Norbert Krug, Thomas Sandstrom, Dominic E. Shaw, Rene Lutter, Louise J. Fleming, Peter H. Howarth, Massimo Caruso, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Diane Lefaudeux, Sven‐Erik Dahlen, Ratko Djukanovic, Peter J. Sterk, Yike Guo, Ian M. Adcock, Kian Fan Chung, and the U‐BIOPRED study group
- Subjects
asthma exacerbations ,severe asthma ,CEACAM5 ,frequent exacerbators ,persistent frequent exacerbators ,Medicine (General) ,R5-920 - Abstract
Abstract Background Exacerbation‐prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. Objectives To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U‐BIOPRED cohort. Methods We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE,
- Published
- 2022
- Full Text
- View/download PDF
9. Abstracts from the 3rd International Severe Asthma Forum (ISAF)
- Author
-
M. E. Ketelaar, K. Van De Kant, F. N. Dijk, E. M. M. Klaassen, N. Grotenboer, M. C. Nawijn, E. Dompeling, G. H. Koppelman, Clare Murray, Philip Foden, Lesley Lowe, Hannah Durrington, Adnan Custovic, Angela Simpson, Andrew J. Simpson, Dominick E. Shaw, Ana R. Sousa, Louise J. Fleming, Graham Roberts, Ioannis Pandis, Aruna T. Bansal, Julie Corfield, Scott Wagers, Ratko Djukanovic, Kian Fan Chung, Peter J. Sterk, Jorgen Vestbo, Stephen J. Fowler, S. J. Tebbutt, A. Singh, C. P. Shannon, Y. W. Kim, C. X. Yang, G. M. Gauvreau, J. M. Fitzgerald, L. P. Boulet, P. M. O’Byrne, N. Begley, A. Loudon, D. W. Ray, Selene Baos, Lucía Cremades, David Calzada, Carlos Lahoz, Blanca Cárdaba, Kewal Asosingh, Chris Lauruschkat, Kimberly Queisser, Nicholas Wanner, Kelly Weiss, Weiling Xu, Serpil Erzurum, Milena Sokolowska, Li-Yuan Chen, Yueqin Liu, Asuncion Martinez-Anton, Carolea Logun, Sara Alsaaty, Rosemarie Cuento, Rongman Cai, Junfeng Sun, Oswald Quehenberger, Aaron Armando, Edward Dennis, Stewart Levine, James Shelhamer, Kilyong Choi, Snezhina Lazova, Penka Perenovska, Dimitrinka Miteva, Stamatios Priftis, Guergana Petrova, Vassil Yablanski, Evgeni Vlaev, Hristina Rafailova, Takashi Kumae, L. J. Holmes, J. Yorke, D. M. Ryan, Sasawan Chinratanapisit, Khlongtip Matchimmadamrong, Jitladda Deerojanawong, Wissaroot Karoonboonyanan, Paskorn Sritipsukho, Vania Youroukova, Denitsa Dimitrova, Yanina Slavova, Spaska Lesichkova, Iren Tzocheva, Snezhana Parina, Svetla Angelova, Neli Korsun, Mihai Craiu, Iustina Violeta Stan, Matea Deliu, Tolga Yavuz, Matthew Sperrin, Umit M. Sahiner, Danielle Belgrave, Cansin Sackesen Sackesen, Ömer Kalayci, Petar Velikov, Tsvetelina Velikova, Ekaterina Ivanova-Todorova, Kalina Tumangelova-Yuzeir, Dobroslav Kyurkchiev, Spyridon Megremis, Bede Constantinides, Alexandros Georgios Sotiropoulos, Paraskevi Xepapadaki, David Robertson, Nikolaos Papadopoulos, Maxim Wilkinson, Craig Portsmouth, David Ray, Royston Goodacre, Anna Valerieva, Irina Bobolea, Daiana Guillén Vera, Gabriel Gonzalez-Salazar, Carlos Melero Moreno, Consuelo Fernandez Rodriguez, Natividad De Las Cuevas Moreno, R. Wang, I. Satia, R. Niven, J. A. Smith, T. Southworth, J. Plumb, V. Gupta, J. Pearson, I. Ramis, M. D. Lehner, M. Miralpeix, D. Singh, Imran Satia, Mark Woodhead, Paul O’Byrne, Jaclyn Ann Smith, Cecilia Forss, Peter Cook, Sheila Brown, Freya Svedberg, Katherine Stephenson, Margherita Bertuzzi, Elaine Bignell, Malin Enerbäck, Danen Cunoosamy, Andrew Macdonald, Caini Liu, Liang Zhu, Kiochi Fukuda, Cunjin Zhang, Suidong Ouyang, Xing Chen, Luke Qin, Suguna Rachakonda, Mark Aronica, Jun Qin, Xiaoxia Li, Marie-Chantal Larose, Anne-Sophie Archambault, Véronique Provost, Jamila Chakir, Michel Laviolette, Nicolas Flamand, Nicola Logan, Dominik Ruckerl, Judith E. Allen, Tara E. Sutherland, E. Hamelmann, C. Vogelberg, S. Goldstein, G. E. Azzi, M. Engel, R. Sigmund, S. J. Szefler, Raquel Mesquita, Luis Coentrão, Rui Veiga, José-Artur Paiva, Roberto Roncon-Albuquerque, Wendy Vargas Porras, Ana González Moreno, Jesus Macías Iglesias, Gustavo Córdova Ramos, Yesenia Peña Acevedo, Miguel Angel Tejedor Alonso, Maria Del Mar Moro Moro, Irena Krcmova, Jakub Novosad, Nicola Alexander Hanania, Marc Massanari, Heike Hecker, Eric Kassel, Craig Laforce, Kathy Rickard, Sanne Snelder, Gert-Jan Braunstahl, T. L. Jones, D. Neville, E. R. Heiden, E. Lanning, T. Brown, H. Rupani, K. S. Babu, A. J. Chauhan, M. Y. Eldegeir, A. A. Chapman, M. Ferwana, and M. Caldron
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2017
- Full Text
- View/download PDF
10. Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps
- Author
-
Larry Borish, Noam A. Cohen, Geoffrey Chupp, Claire Hopkins, Martin Wagenmann, Ana R. Sousa, Steven G. Smith, Jared Silver, Shibing Yang, Bhabita Mayer, Steven W. Yancey, Robert H. Chan, and Wytske Fokkens
- Subjects
Pulmonary and Respiratory Medicine ,Biological Products ,Nasal Polyps ,Adrenal Cortex Hormones ,Immunology ,Chronic Disease ,Immunology and Allergy ,Humans ,Omalizumab ,Sinusitis ,Rhinitis - Abstract
Objective: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. Data Sources: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. Study Selections: Randomized, controlled phase III trials of biologics approved for CRSwNP. Results: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. Conclusion: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.
- Published
- 2022
11. Real‐world characterisation of patients with chronic rhinosinusitis with nasal polyps with and without surgery in England
- Author
-
Victoria S. Benson, Qinggong Fu, Shibing Yang, Ana R. Sousa, Robert H. Chan, Peter Howarth, and Claire Hopkins
- Subjects
Otorhinolaryngology - Published
- 2023
12. The unified airway hypothesis: evidence from specific intervention with anti-interleukin-5 biologic therapy
- Author
-
Claus Bachert, Amber U. Luong, Philippe Gevaert, Joaquim Mullol, Steven G. Smith, Jared Silver, Ana R. Sousa, Peter H. Howarth, Victoria S. Benson, Bhabita Mayer, Robert H. Chan, and William W. Busse
- Subjects
Immunology and Allergy - Published
- 2023
13. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): in-depth sinus surgery analysis
- Author
-
Wytske J. Fokkens, Joaquim Mullol, David Kennedy, Carl Philpott, Veronica Seccia, Robert C. Kern, André Coste, Ana R. Sousa, Peter H. Howarth, Victoria S. Benson, Bhabita Mayer, Steve W. Yancey, Robert Chan, Simon B. Gane, Ear, Nose and Throat, and AII - Inflammatory diseases
- Subjects
refractory ,recurrence ,Immunology ,Immunology and Allergy ,mepolizumab ,chronic rhinosinusitis with nasal polyps ,sinonasal surgery - Abstract
Background: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE. Methods: SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. Results: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan–Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (
- Published
- 2023
14. The roles of eosinophils and interleukin‐5 in the pathophysiology of chronic rhinosinusitis with nasal polyps
- Author
-
Philippe Gevaert, Joseph K. Han, Steven G. Smith, Ana R. Sousa, Peter H. Howarth, Steven W. Yancey, Robert Chan, and Claus Bachert
- Subjects
Inflammation ,monoclonal ,biomarkers ,nasal obstruction ,immunity ,Immunity, Innate ,cytokines ,Eosinophils ,Nasal Polyps ,Otorhinolaryngology ,inflammation ,Chronic Disease ,Eosinophilia ,biological products ,Medicine and Health Sciences ,innate ,Humans ,Cytokines ,antibodies ,Immunology and Allergy ,Lymphocytes ,Inflammation Mediators ,Interleukin-5 ,Sinusitis ,Rhinitis - Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with eosinophilic tissue infiltration linked to type 2 inflammation and characterized by elevated levels of interleukin (IL)-5 and other type 2 inflammatory mediators. Although distinct and overlapping contributions of eosinophils and IL-5 to CRSwNP pathology are still being explored, they are both known to play an important role in NP inflammation. Eosinophils secrete numerous type 2 inflammatory mediators including granule proteins, enzymes, cytokines, chemokines, growth factors, lipids, and oxidative products. IL-5 is critical for the differentiation, migration, activation, and survival of eosinophils but is also implicated in the biological functions of mast cells, basophils, innate lymphoid cells, B cells, and epithelial cells. Results from clinical trials of therapeutics that target type 2 inflammatory mediators (including but not limited to anti-IL-5, anti-immunoglobulin-E, and anti-IL-4/13) may provide further evidence of how eosinophils and IL-5 contribute to CRSwNP. Finally, the association between eosinophilia/elevated IL-5 and greater rates of NP recurrence after endoscopic sinus surgery (ESS) suggests that these mediators may have utility as biomarkers of NP recurrence in diagnosing and assessing the severity of CRSwNP. This review provides an overview of eosinophil and IL-5 biology and explores the literature regarding the role of these mediators in CRSwNP pathogenesis and NP recurrence following ESS. Based on current published evidence, we suggest that although eosinophils play a key role in CRSwNP pathophysiology, IL-5, a cytokine that activates these cells, also represents a pertinent and effective treatment target in patients with CRSwNP.
- Published
- 2022
15. Oropharyngeal Microbiota Clusters in Children with Asthma/Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways and Exacerbations Risk
- Author
-
Mahmoud I. Abdel-Aziz, Jonathan Thorsen, Simone Hashimoto, Susanne J H Vijverberg, Anne H Neerincx, Paul Brinkman, Wim van Aalderen, Jakob Stokholm, Morten Arendt Rasmussen, Michael Roggenbuck-Wedemeyer, Nadja H Vissing, Martin Steen Mortensen, Asker Daniel Brejnrod, Louise J Fleming, Clare S Murray, Stephen J Fowler, Urs Frey, Andrew Bush, Florian Singer, Gunilla Hedlin, Björn Nordlund, Dominick E Shaw, Kian Fan Chung, Ian M Adcock, Ratko Djukanovic, Charles Auffray, Aruna T Bansal, Ana R Sousa, Scott S Wagers, Bo Lund Chawes, Klaus Bønnelykke, Søren Johannes Sørensen, Aletta D. Kraneveld, Peter J Sterk, Graham Roberts, Hans Bisgaard, and Anke H. Maitland-van der Zee
- Subjects
Pulmonary and Respiratory Medicine ,Critical Care and Intensive Care Medicine ,610 Medicine & health - Abstract
RATIONALE Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. OBJECTIVE To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. METHODS Oropharyngeal swabs, from the Unbiased BIOmarkers for the Prediction of REspiratory Disease outcomes pediatric asthma/wheezing cohort, were characterized by 16S rRNA gene sequencing and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores (ESs) of the MSigDB Hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessing the frequency of exacerbations. MEASUREMENTS AND MAIN RESULTS Oropharyngeal samples of 241 children (age range: 1-17 years, 40% female) revealed 4 taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia and Haemophilus, respectively. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1 % predicted post-salbutamol, and the annual asthma exacerbation frequency during follow-up. The Veillonella-cluster was the most allergic and included highest percentage of children with ≥2 exacerbations/year during follow-up. The oropharyngeal clusters were different in the ESs of transforming growth factor β (highest in Veillonella-cluster) and Wnt/β-Catenin signaling (highest in Haemophilus-cluster) transcriptomic pathways in blood (all q-values < 0.05). CONCLUSION The analysis of the oropharyngeal microbiota of children with asthma/wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with exacerbations' risk and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiological insights and potentially new treatment approaches.
- Published
- 2023
- Full Text
- View/download PDF
16. Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort.
- Author
-
Rosalia Emma, Aruna T Bansal, Johan Kolmert, Craig E Wheelock, Swen-Erik Dahlen, Matthew J Loza, Bertrand De Meulder, Diane Lefaudeux, Charles Auffray, Barbro Dahlen, Per S Bakke, Pascal Chanez, Stephen J Fowler, Ildiko Horvath, Paolo Montuschi, Norbert Krug, Marek Sanak, Thomas Sandstrom, Dominick E Shaw, Louise J Fleming, Ratko Djukanovic, Peter H Howarth, Florian Singer, Ana R Sousa, Peter J Sterk, Julie Corfield, Ioannis Pandis, Kian F Chung, Ian M Adcock, René Lutter, Lorena Fabbella, Massimo Caruso, and U-BIOPRED Study Group
- Subjects
Medicine ,Science - Abstract
Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF2α; IS-transcriptomics; BB-transcriptomics; BBr-transcriptomics). Urinary 8-iso-PGF2α was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF2α was increased in SAs/ex, median (IQR) = 31.7 (24.5-44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6-36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4-47.7), vs. ESA, median (IQR) = 29.4 (22.3-40.5), and NSA, median (IQR) = 26.5 (19.6-16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF2α in the smokers/ex-smokers group. Trial registration ClinicalTrials.gov-Identifier: NCT01976767.
- Published
- 2018
- Full Text
- View/download PDF
17. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial
- Author
-
Joseph K Han, Claus Bachert, Wytske Fokkens, Martin Desrosiers, Martin Wagenmann, Stella E Lee, Steven G Smith, Neil Martin, Bhabita Mayer, Steven W Yancey, Ana R Sousa, Robert Chan, Claire Hopkins, Cecilia Ahlström Emanuelsson, Ledit Ardusso, Michael Armstrong, Philip Bardin, Sara Barnes, Miguel Bergna, Christian Betz, Achim Beule, James Blotter, Valeriu Bronescu, Matthew Brown, Sean Carrie, Adam Chaker, Hyung-Ju Cho, Marie-Noëlle Corriveau, Timothy Courville, Mandy Cuevas, Cecelia Damask, Adam DeConde, Jaime Del Carpio, María De Salvo, Hun-Jong Dhong, Stephen Durham, Anton Edin, Dale Ehmer Jr, Pedro Elías, Adil Fatakia, Christine Franzese, Simon Gane, Gabriel García, Andrew Gillman, Moritz Groeger, Richard Harvey, Johan Hellgren, Thomas Higgins, Jonathan Hobson, Mattias Jangard, Arif Janjua, Naveed Kara, Sergey Karpischenko, Edward Kerwin, Fatimat Khanova, Shaun Kilty, Chang-Hoon Kim, Seontae Kim, Ludger Klimek, Craig LaForce, Samuel Leong, Bradley Marple, Anders Mårtensson, Jorge Maspero, Neil Massey, Jonathan Matz, Chad McDuffie, Corina Mella, Steven Miller, Ekaterina Mirzabekyan, Jonathan Moss, Nayla Mumneh, Robert Nathan, Adriana Neagos, Heidi Olze, Andrey Ovchinnikov, Randall Ow, Dmitriy Polyakov, Doinel Radeanu, Chae-Seo Rhee, Ramón Rojas, Jeffrey Rosenbloom, Sergei Ryazantsev, Chady Sader, Pablo Saez Scherbovsky, Guy Scadding, Rodney Schlosser, Heena Shah-Patel, Ronald Shealy, Ayesha Siddiqi, Stacey Silvers, Narinder Singh, Doron Sommer, Weily Soong, Leigh Sowerby, Peter Spafford, Catalin Stefan, Richard Sterling, Valeriy Svistushkin, Neetu Talreja, Galina Tarasova, Martha Tarpay, Alberto Tolcachier, Karin Toll Toll, Carolina van Schaik, Luke Webb, H James Wedner, Luis Wehbe, Soo Whan Kim, Barbara Wollenberg, Simon Wright, Vladimir Yakusevich, Anahí Yañez, Yury Yarin, David Yen, Hyo Yeol Kim, Ear, Nose and Throat, and AII - Inflammatory diseases
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,Nasal cavity ,medicine.medical_specialty ,Adolescent ,Visual analogue scale ,Population ,Mometasone furoate ,Antibodies, Monoclonal, Humanized ,Placebo ,03 medical and health sciences ,Nasal Polyps ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Humans ,Nasal polyps ,030212 general & internal medicine ,education ,education.field_of_study ,business.industry ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,030228 respiratory system ,Synapses ,Nasal administration ,business ,Mepolizumab ,medicine.drug - Abstract
Background: Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians −0·73, 95% CI −1·11 to −0·34; p
- Published
- 2021
18. Medication Adherence in Patients With Severe Asthma Prescribed Oral Corticosteroids in the U-BIOPRED Cohort
- Author
-
P. J. Sterk, John H. Riley, Thomas Sandström, Anna Selby, Laurie Pahus, C. Auffray, Ioannis Pandis, Julie Corfield, R. Djukanovic, K. Sun, Massimo Caruso, Jørgen Vestbo, Matthew J. Loza, Andrew J. Simpson, Dominic Burg, I.M. Adcock, S. Bates, Scott Wagers, Ana R. Sousa, J. Corfield, Ariane H. Wagener, René Lutter, Barbro Dahlén, Ratko Djukanovic, G. Praticò, I. Pandis, N. Mores, G. Hedlin, Navin Rao, I. Horváth, Alexander Mazein, B. De Meulder, Richard G. Knowles, John-Olof Thörngren, Wolfgang Seibold, P H Howarth, Victoria M. Goss, Cristina Gómez, Clare S. Murray, Paul Brinkman, Ildiko Horvath, Anthony D. Postle, M. Caruso, Martina Gahlemann, M. Puig Valls, F.K. Chung, P. Montuschi, Dominick E. Shaw, Kai Sun, Aruna T. Bansal, Fahad Alahmadi, Amphun Chaiboonchoe, Graham Roberts, Kian Fan Chung, Yike Guo, H. Ahmed, Thomas Geiser, Klaus Bønnelykke, M. Miralpeix, Simone Hashimoto, Diane Lefaudeux, S.S. Wagers, D. Erzen, B. Thornton, Florian Singer, Louise Fleming, Stephen J. Fowler, Neil Fitch, P. Bakke, Craig E. Wheelock, Nadja Hawwa Vissing, Tim Higenbottam, Jamie Matthews, F. Singer, S.E. Dahlén, Sarah Masefield, Roelinde Middelveld, Jens M. Hohlfeld, Anthony V. D'Amico, Paul Skipp, W.M.C. van Aalderen, Alan J. Knox, Sven-Erik Dahlén, Andrew Bush, A.T. Bansal, Pieter-Paul Hekking, Joost Brandsma, Stewart Bates, L.J. Fleming, Norbert Krug, N. Krug, Magnus Ericsson, J. Riley, P. Powel, Jacek Musiał, Amanda Roberts, Peter J. Sterk, Ian M. Adcock, Pascal Chanez, Cecile T.J. Holweg, F. Baribaud, Stelios Pavlidis, Veit J. Erpenbeck, Z. Weiszhart, C.E. Wheelock, Ralf Sigmund, James P.R. Schofield, Alexander Manta, Andrea Meiser, Susan J. Wilson, Jeanette Bigler, G. Roberts, M. van Geest, Hans Bisgaard, Urs Frey, Michael Boedigheimer, Per Bakke, Chris Compton, Enrica Bucchioni, Paolo Montuschi, David Myles, E.H.D. Bel, Anna James, Elena Formaggio, Anthony Rowe, Dominic E. Shaw, J. Haughney, P. Chanez, A.R. Sousa, S.J. Fowler, K. Fichtner, B. Dahlèn, Publica, Commission of the European Communities, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Pulmonology, AII - Inflammatory diseases, and Paediatric Pulmonology
- Subjects
Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,urinary corticosteroids ,Prescription Drugs ,Settore BIO/14 - FARMACOLOGIA ,medicine.drug_class ,[SDV]Life Sciences [q-bio] ,Urinary system ,Respiratory System ,Administration, Oral ,610 Medicine & health ,Critical Care and Intensive Care Medicine ,Hospital Anxiety and Depression Scale ,Medication Adherence ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Interquartile range ,Internal medicine ,Surveys and Questionnaires ,Administration, Inhalation ,Medicine ,Humans ,030212 general & internal medicine ,adherence ,Glucocorticoids ,ComputingMilieux_MISCELLANEOUS ,U-BIOPRED Study Group ,Asthma ,Dose-Response Relationship, Drug ,business.industry ,1103 Clinical Sciences ,Middle Aged ,asthma ,medicine.disease ,030228 respiratory system ,Cohort ,Prednisolone ,Quality of Life ,Corticosteroid ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity? Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry. Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels. Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.
- Published
- 2021
19. Type 2‐low asthma phenotypes by integration of sputum transcriptomics and serum proteomics
- Author
-
Sven-Erik Dahlén, Kai Sun, Nazanin Zounemat Kermani, Stephany Sánchez-Ovando, Åsa M. Wheelock, John H. Riley, Craig E. Wheelock, Yike Guo, Stelios Pavlidis, Charles Auffray, Chih-Hsi Kuo, Peter J. Sterk, Bertrand De Meulder, Sharon Mumby, Kian Fan Chung, Peter A. B. Wark, Jodie L. Simpson, Jim Schofield, Paul Agapow, Ian M. Adcock, Matthew J. Loza, Katherine J. Baines, Kai Sen Tan, Ratko Djukanovic, Frédéric Baribaud, Mansoor Saqi, Ana R. Sousa, AII - Inflammatory diseases, Pulmonology, and Commission of the European Communities
- Subjects
Proteomics ,Allergy ,Serum proteomics ,precision medicine ,Systems biology ,Asthma phenotypes ,Immunology ,U-BIOPRED Project Team ,Transcriptome ,Humans ,Immunology and Allergy ,Medicine ,Asthma ,Science & Technology ,business.industry ,Sputum ,systems biology ,bioinformatics ,asthma ,Precision medicine ,medicine.disease ,Phenotype ,1107 Immunology ,endotypes ,medicine.symptom ,business ,Life Sciences & Biomedicine ,Biomarkers - Published
- 2020
20. Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
- Author
-
Peter J. Sterk, Nazanin Zounemat Kermani, Ian M. Adcock, Pascal Chanez, Florian Singer, Stewart Bates, Magnus Ericsson, John H. Riley, Jessica Lasky-Su, Romanas Chaleckis, Ildiko Horvath, Hector Gallart-Ayala, Stephen J. Fowler, Craig E. Wheelock, Norbert Krug, Henric Olsson, Stacey N. Reinke, Jacek Musiał, Peter H. Howarth, Matthew J. Loza, Kian Fan Chung, Barbro Dahlén, Thomas Geiser, Massimo Caruso, David I. Broadhurst, Cristina Gómez, Dominick E. Shaw, Johan Kolmert, Per Bakke, Angelica Tiotiu, Paolo Montuschi, Sile Hu, Ratko Djukanovic, Ana R. Sousa, Sven-Erik Dahlén, Frédéric Baribaud, James Scholfield, Shama Naz, Åsa M. Wheelock, Anders Lundqvist, Annelie F. Behndig, Marika Ström, Pulmonology, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Publica
- Subjects
severe asthma ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Settore BIO/14 - FARMACOLOGIA ,[SDV]Life Sciences [q-bio] ,Respiratory Medicine and Allergy ,Urinary system ,610 Medicine & health ,Urine ,Disease ,SLC22A5 ,Severity of Illness Index ,Gastroenterology ,U_BIOPRED ,03 medical and health sciences ,0302 clinical medicine ,Adrenal Cortex Hormones ,Carnitine ,Internal medicine ,medicine ,Humans ,Anti-Asthmatic Agents ,030212 general & internal medicine ,Solute Carrier Family 22 Member 5 ,Lungmedicin och allergi ,Asthma ,urinary metabotype ,biology ,business.industry ,medicine.disease ,3. Good health ,Cross-Sectional Studies ,030228 respiratory system ,Cohort ,biology.protein ,Sputum ,medicine.symptom ,business ,medicine.drug - Abstract
IntroductionAsthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsA total of 90 metabolites were identified, with 40 significantly altered (p−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
- Published
- 2022
21. Comparative clinical pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate
- Author
-
Peter T, Daley-Yates, Amanda, Deans, Rashmi, Mehta, and Ana R, Sousa
- Subjects
Pulmonary and Respiratory Medicine ,Hypothalamo-Hypophyseal System ,Cross-Over Studies ,Hydrocortisone ,Biochemistry (medical) ,Pituitary-Adrenal System ,Androstadienes ,Receptors, Glucocorticoid ,Double-Blind Method ,Administration, Inhalation ,Humans ,Fluticasone ,Pharmacology (medical) ,Mometasone Furoate - Abstract
To investigate the pharmacokinetics and effects on the hypothalamic-pituitary-adrenal (HPA) axis of mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF).Study 1: Fourteen healthy participants received inhaled and intravenous MF (inhaled dose via Twisthaler) and FP (inhaled dose via Diskus), both given at 400 μg, using a randomised, single-dose, four-way crossover design. Study 2: Twenty-seven participants with mild to moderate asthma, who discontinued their corticosteroid medication for 5 days to obtain a baseline 24 h serum cortisol, received inhaled MF Twisthaler and FP Diskus, both given at 400 μg twice daily (BID), using a randomised, 14-day repeat dose, two-way crossover design. Study 3: Forty-four healthy participants were randomised to a double-blind, placebo-controlled, five-period crossover study where the following treatments were administered via the inhaled route for 7 days: FP Diskus (250, 500, 1000 μg BID), FF Diskus (100, 200, 400, 800, 1600 μg once daily [QD]) or placebo Diskus. In each study, 24-h serial blood samples were collected and assayed to assess concentrations of MF, 6β-hydroxy mometasone, mometasone, FP, FF and cortisol. Pharmacokinetic and serum cortisol parameters were estimated as geometric means and 95% confidence intervals (CI).Study 1: For intravenous MF and FP, respectively: absolute bioavailability was 11.4% (95% CI: 7.5, 17.6) and 7.8% (6.3, 9.6); plasma clearance was 47 L/h (41, 52) and 60 L/h (52, 69); half-life was 7.4 h (6.9, 8.0) and 7.2 h (6.5, 8.0); and volume of distribution was 499 L (439, 567) and 623 L (557, 698). Inhalation of single dose MF or FP did not significantly affect serum cortisol (10% reduction from baseline), whereas intravenous administration of MF or FP each changed serum cortisol by approximately -50% from baseline. Study 2: For MF and FP, respectively: area under the curve up to the last measurable concentration on Day 1 was 421 pg h/mL (270, 659) and 248 pg h/mL (154, 400), and on Day 14 was 1092 pg h/mL (939, 1269) and 591 pg h/mL (501, 696); absolute bioavailability was 12.8% (11.2, 14.2) and 8.9% (7.7, 10.2). On Day 14, 24-h serum cortisol change from baseline was -35% (-44%, -26%) and -18% (-28%, -5%) for MF and FP, respectively; the reduction was significantly greater for MF than FP (ratio for geometric adjusted mean serum cortisol concentration: 1.28 [1.04, 1.56]). Low plasma concentrations of 6β-hydroxy mometasone were detected after intravenous dosing (Study 1) and after multiple inhaled dosing (Study 2); mometasone was not detected in any samples. Study 3: Inhaled FP and FF had similar systemic bioavailability estimates (12.0% [11.0, 13.2] and 15.0% [12.0, 17.3], respectively), but a differential effect on the HPA axis which was in agreement with the known 1.7-fold higher glucocorticoid receptor-binding affinity of FF versus FP. However, for FP 250 μg BID and FF 100, 200 and 400 μg QD, reduction in serum cortisol was not significantly different from placebo. For higher doses, FP 500 and 1000 μg BID, and FF 800 and 1600 μg QD, changes in serum cortisol concentration relative to placebo were -30%, -70%, -41% and -90%, respectively. Repeat inhaled dosing of FP 1000 μg/day (within the therapeutic dose range) resulted in comparable cortisol suppression to MF in the therapeutic range (30% reduction); whereas for FF this occurred at more than 3-fold above the therapeutic dose range (644 μg/day).Single inhaled and intravenous doses of MF and FP (400 μg) resulted in similar bioavailability and reductions in serum cortisol. Repeat dosing of inhaled MF and FP in the therapeutic range (800 μg/day) resulted in greater systemic exposure for MF, and a 35% reduction in serum cortisol that was 2-fold greater than for FP. The higher glucocorticoid receptor-binding affinity and bioavailability, lower clearance and the presence of active metabolites may contribute to the greater systemic exposure and effect on cortisol for MF. Repeat dosing of inhaled FP and FF resulted in similar systemic bioavailability but differed in terms of the dose required for comparable cortisol suppression to MF in the therapeutic range. Unlike FP and FF, MF has active metabolites that may contribute to its systemic effects, while device/formulation performance differences also exist between MF-containing products.
- Published
- 2022
22. Late Breaking Abstract - Response to mepolizumab in patients with severe CRSwNP using EUFOREA 2021 criteria
- Author
-
Steven G. Smith, Claus Bachert, Shibing Yang, Steve Yancey, W. J. Fokkens, Robert Chan, Stella E. Lee, Claire Hopkins, Ana R. Sousa, Joseph K. Han, Zuzana Diamant, Bhabita Mayer, and Valerie J. Lund
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,In patient ,business ,Mepolizumab ,medicine.drug - Published
- 2021
23. A multi-omics approach to delineate sputum microbiome-associated asthma inflammatory phenotypes
- Author
-
Peter J. Sterk, Mahmoud I. Abdel-Aziz, Ian M. Adcock, Pascal Chanez, Stephen J. Fowler, Stewart Bates, Bertrand De Meulder, Anne H. Neerincx, René Lutter, Scott Wagers, Ildiko Horvath, Kai Sun, Paul Brinkman, Massimo Caruso, John H. Riley, Mohib Uddin, Aletta D. Kraneveld, Paolo Montuschi, Ana R. Sousa, Kian Fan Chung, Åsa M. Wheelock, Ratko Djukanovic, Charles Auffray, Paul Skipp, Jacek Musiał, Marek Sanak, Dominick E. Shaw, Aruna T. Bansal, Ariane H. Wagener, Susanne J. H. Vijverberg, Norbert Krug, Julie Corfield, Anke H Maitland-van der Zee PharmD, Thomas Sandström, Peter H. Howarth, Pediatric surgery, Pulmonary medicine, Publica, Graduate School, Pulmonology, AII - Cancer immunology, AII - Inflammatory diseases, APH - Personalized Medicine, AII - Infectious diseases, and Paediatric Pulmonology
- Subjects
Pulmonary and Respiratory Medicine ,business.industry ,Microbiota ,MEDLINE ,Sputum ,medicine.disease ,Phenotype ,Asthma ,Eosinophils ,Immunology ,Medicine ,Multi omics ,Humans ,Microbiome ,medicine.symptom ,business - Abstract
Asthma is a heterogeneous disease with multiple clinical presentations (phenotypes). Neutrophilic asthma is characterised by increased sputum neutrophils and generally has a poor response to corticosteroids and limited other therapeutic options. Neutrophilia originates from different factors, including the defective resolution of inflammation or bacterial infections. An association between airway bacterial imbalance (disturbance) and the neutrophilic phenotype has been reported, suggesting that airway microbiota composition is involved in neutrophilic asthma. Rather than being a separate entity, neutrophilic asthma may be in part, an alliance between innate immunity and microbiota composition that prompts protective mechanisms against invading pathogens.
- Published
- 2021
24. Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count
- Author
-
Claus Bachert, Ana R. Sousa, Joseph K. Han, Rodney J. Schlosser, Leigh J. Sowerby, Claire Hopkins, Jorge F. Maspero, Steven G. Smith, Oliver Kante, Despina E. Karidi-Andrioti, Bhabita Mayer, Robert H. Chan, Steve W. Yancey, and Adam M. Chaker
- Subjects
nasal polyps ,type 2 inflammation ,chronic rhinosinusitis ,blood eosinophils ,Immunology ,mepolizumab ,Comorbidity ,Antibodies, Monoclonal, Humanized ,Asthma ,AERD ,Eosinophils ,Nasal Polyps ,Treatment Outcome ,Chronic Disease ,Medicine and Health Sciences ,Humans ,sinus surgery ,Immunology and Allergy ,Asthma, Aspirin-Induced ,biologic therapy ,Nasal Obstruction ,Sinusitis - Abstract
Background: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. Objective: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). Methods: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. Results: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts >150 or >300 cells/mL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (150 cells/mL: 49.5% vs 28.1%; 300 cells/mL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. Conclusions: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.
- Published
- 2022
25. Airway Elastin is increased in severe asthma and relates to proximal wall area : histological and computed tomography findings from the U-BIOPRED severe asthma study
- Author
-
Bo Billing, Peter J. Sterk, Ana R. Sousa, Dominick E. Shaw, Norbert Krug, Susan J. Wilson, Christopher E. Brightling, Simonetta Baldi, Helen M Pickett, Thomas Sandstrӧm, Kian Fan Chung, Peter H. Howarth, Barbro Dahlén, Jonathan Ward, Ratko Djukanovic, and Pulmonology
- Subjects
0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Biopsy ,Respiratory Medicine and Allergy ,Immunology ,Bronchi ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Submucosa ,Bronchoscopy ,medicine ,Immunology and Allergy ,Humans ,Asthma ,Lungmedicin och allergi ,Lamina reticularis ,Hyperplasia ,biology ,business.industry ,Mucin ,Mucins ,Middle Aged ,medicine.disease ,Elastin ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Case-Control Studies ,biology.protein ,Airway Remodeling ,Female ,Smooth muscle hypertrophy ,Collagen ,Goblet Cells ,Airway ,business ,Tomography, X-Ray Computed - Abstract
Background: Airway remodelling, which may include goblet cell hyperplasia / hypertrophy, changes in epithelial integrity, accumulation of extracellular matrix components, smooth muscle hypertrophy and thickening of the lamina reticularis, is a feature of severe asthma and contributes to the clinical phenotype. Objective: Within the U-BIOPRED severe asthma study, we have assessed histological elements of airway remodelling and their relationship to computed tomography (CT) measures of proximal airway dimensions. Methods: Bronchial biopsies were collected from two severe asthma groups, one non-smoker (SAns, n=28) and one current/ex-smoker (SAs/ex, n=13), and a mild-moderate asthma group (MMA, n=28) classified and treated according to GINA guidelines, plus a healthy control group (HC, n=33). A Movat’s pentachrome technique was used to identify mucin, elastin and total collagen in these biopsies. The number of goblet cells (mucin+) were counted as a percentage of the total number of epithelial cells and the percentage mucin epithelial area measured. The percentage area of elastic fibres and total collagen within the submucosa were also measured, and the morphology of the elastic fibres classified. Participants in the asthma groups also had a CT scan to assess large airway morphometry.Results: The submucosal tissue elastin percentage was higher in both severe asthma groups (16.1% SAns, 18.9% SAs/ex) compared to the HC (9.7%) but did not differ between asthma groups. There was a positive relationship between elastin and airway wall area measured by CT (n= 18-20, rho=0.544, p=0.024), which also related to an increase in elastic fibres with a thickened lamellar morphological appearance. Mucin epithelial area and total collagen were not different between the four groups. Due to small numbers of suitable CT scans it was not feasible to compare airway morphometry between the asthma groups. Conclusion: These findings identify a link between extent of elastin deposition and airway wall thickening in severe asthma.
- Published
- 2021
26. Congenital long QT syndrome presenting as unexplained bradycardia
- Author
-
Rita Ataíde Silva, Ana R Sousa, Maria Salomé Leal de Carvalho, and Rui Anjos
- Subjects
Electrocardiography ,Long QT Syndrome ,Pacemaker, Artificial ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,Bradycardia ,Infant, Newborn ,Humans ,Infant ,Arrhythmias, Cardiac ,cardiovascular diseases ,General Medicine - Abstract
Congenital long QT syndrome (LQTS) is a genetically autosomal heterogeneous disorder of the ion channels and causes about 10% of sudden death infant syndrome in newborns. Its estimated prevalence is approximately 1 in 2500, probably underestimated because of its clinical heterogenicity. Few cases of neonatal LQTS have been reported. In 4% of them, life-threatening arrhythmic events can be the first manifestation of LQTS. The authors report two cases of neonatal LQTS with heterogeneous genetic mutations. Both manifested by bradycardia, one since fetal life. One case had serious arrhythmias during beta blocker therapeutic establishment needing a pacemaker implantation. Genetic mutations found were not the most frequently described in association with neonatal bradycardia, thus the importance of this report. Presentation with bradycardia is relatively frequent in neonatal period, thus LQTS should be actively investigated in neonates with unexplained bradycardia. Beta blocker therapy reduces QTc and avoids arrhythmic events and sudden death.
- Published
- 2022
27. COPD phenotypes by computed tomography and ventilatory response to exercise
- Author
-
Fernando Barata, Ana Elizabeth Figueiredo, Ana R. Sousa, Margarida Valério, João Nunes Caldeira, and Cidália Rodrigues
- Subjects
medicine.medical_specialty ,COPD ,medicine.diagnostic_test ,business.industry ,Copd patients ,Mixed type ,Computed tomography ,Cardiopulmonary exercise testing ,medicine.disease ,respiratory tract diseases ,Internal medicine ,Hounsfield scale ,Cardiology ,Medicine ,business ,Aerobic capacity - Abstract
Introduction: CT phenotypic patterns of chronic obstructive pulmonary (COPD) defining emphysema-dominant versus airway-dominant groups identify different clinical features of disease. The impact of these variables on the physiological response to exercise has been a great deal of research. Objective: To evaluate the relationship between CT phenotyping of COPD patients and the ventilatory response during cardiopulmonary exercise testing (CPET). Methods: Patients with COPD were classified into 4 phenotypes based on CT using two cut-offs: percentage of low attenuation area (%LAA) less than a threshold of -950 Hounsfield units of 15% and median value of the percentage of bronchial mean wall area (MWA%). Results: Eighty COPD patients (78.8% males, median age 65±1.3 years) were enrolled in the study. Based on CT phenotype, 25 (31,3%) patients were classified as normal, 27 (33,8%) air dominant, 17 (21,3%) emphysema dominant and 11 (13,8%) mixed type. The emphysema dominant phenotype showed the lowest peak aerobic capacity (VO2), the highest ventilatory equivalent for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2) among the four groups (p Conclusion: CPET parameters such as aerobic capacity and ventilatory demands (VE/VO2, VE/VCO2) were associated with emphysematous change. These results suggested that phenotyping of CT may help predicting ventilatory response to exercise in COPD patients.
- Published
- 2020
28. Urinary Leukotriene E 4 and Prostaglandin D 2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study
- Author
-
Johan Kolmert, Cristina Gómez, David Balgoma, Marcus Sjödin, Johan Bood, Jon R. Konradsen, Magnus Ericsson, John-Olof Thörngren, Anna James, Maria Mikus, Ana R. Sousa, John H. Riley, Stewart Bates, Per S. Bakke, Ioannis Pandis, Massimo Caruso, Pascal Chanez, Stephen J. Fowler, Thomas Geiser, Peter Howarth, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Annelie Behndig, Dominick E. Shaw, Richard G. Knowles, Cécile T. J. Holweg, Åsa M. Wheelock, Barbro Dahlén, Björn Nordlund, Kjell Alving, Gunilla Hedlin, Kian Fan Chung, Ian M. Adcock, Peter J. Sterk, Ratko Djukanovic, Sven-Erik Dahlén, Craig E. Wheelock, H. Ahmed, C. Auffray, A. T. Bansal, E. H. Bel, J. Bigler, B. Billing, F. Baribaud, H. Bisgaard, M. J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, A. Chaiboonchoe, C. H. Compton, J. Corfield, D. Cunoosamy, A. D’Amico, B. De Meulder, V. J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L. J. Fleming, E. Formaggio, U. Frey, M. Gahlemann, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, P. W. Hekking, T. Higenbottam, J. M. Hohlfeld, A. J. Knox, N. Lazarinis, D. Lefaudeux, M. J. Loza, R. Lutter, A. Manta, S. Masefield, J. G. Matthews, A. Mazein, A. Meiser, R. J. M. Middelveld, M. Miralpeix, N. Mores, C. S. Murray, J. Musial, D. Myles, L. Pahus, S. Pavlidis, A. Postle, P. Powel, G. Praticò, M. PuigValls, N. Rao, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J. P. R. Schofield, W. Seibold, A. Selby, R. Sigmund, F. Singer, P. J. Skipp, M. Smicker, K. Sun, B. Thornton, M. Uddin, W. M. van Aalderen, M. van Geest, J. Vestbo, N. H. Vissing, A. H. Wagener, S. S. Wagers, Z. Weiszhart, S. J. Wilson, J. Östling, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
- Subjects
Male ,Severe asthma ,Metabolite ,type 2 inflammation ,Respiratory Medicine and Allergy ,[SDV]Life Sciences [q-bio] ,Physiology ,Omalizumab ,Critical Care and Intensive Care Medicine ,chemistry.chemical_compound ,0302 clinical medicine ,030212 general & internal medicine ,Child ,ComputingMilieux_MISCELLANEOUS ,mass spectrometry ,Lungmedicin och allergi ,2. Zero hunger ,Leukotriene E4 ,Prostaglandin D2 ,Type 2 inflammation ,Middle Aged ,respiratory system ,3. Good health ,medicine.anatomical_structure ,Prednisolone ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.drug ,Pulmonary and Respiratory Medicine ,Adult ,severe asthma ,Settore BIO/14 - FARMACOLOGIA ,Urinary system ,U-BIOPRED ,Asthma and Allergy ,03 medical and health sciences ,Correspondence ,medicine ,Humans ,Asthma ,Inflammation ,Mass spectrometry ,business.industry ,Original Articles ,Eosinophil ,medicine.disease ,respiratory tract diseases ,urinary eicosanoid metabolites ,030228 respiratory system ,chemistry ,Diabetes Mellitus, Type 2 ,Exhaled nitric oxide ,Prostaglandins ,Urinary eicosanoid metabolites ,business ,Biomarkers - Abstract
Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE 2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE 2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE 4 and the PGD 2 metabolite 2,3-dinor-11β-PGF 2α. High concentrations of LTE 4 and PGD 2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).
- Published
- 2020
29. Discordant use of short-acting β
- Author
-
Olga, Gorlanova, Eveline, Tischhauser, Ian M, Adcock, Kian Fan, Chung, Louise, Fleming, Delphine, Meier, Peter J, Sterk, Graham, Roberts, Amanda, Roberts, Florian, Singer, Ana R, Sousa, Mohib, Uddin, and Urs, Frey
- Published
- 2020
30. Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe
- Author
-
Andreia Francisco, Phuoc Duong, Shalan Uaid Fadl, Karl Viktor Perminow, Owen Miller, Vladislav Vukomanovic, Marisa Vieira, Gabriela Doros, Savina Mannarino, Israel Valverde, Francisco Gonzalez Barlatay, Maria Ilina, Ornella Milanesi, Beata Kucińska, Irene M. Kuipers, Antigoni Deri, Fernando Centeno, Susana Maria Rey-García, Zdenka Reinhardt, Victoria C. Ziesenitz, Simona Anna Marcora, Ana R. Sousa, Begoña Manso, Moises Rodriguez-Gonzalez, Jussi Niemelä, Jelena Hubrechts, Cecilia Lazea, Gernot Grangl, Joan Sanchez-de-Toledo, Almudena Ortiz-Garrido, Ferran Gran, Daniël De Wolf, Giulia Bordin, Abigail Sharpe, Francesca Cairello, Bernadette Brent, Gauri Nepali, Isabelle Loeckx, Paraskevi Theocharis, Sylvie Di Filippo, Colin J. McMahon, Ashish Chikermane, Emanuela Valsangiacomo-Buchel, Giridhar Soda, Marie-Christine Seghaye, Fatima Pinto, Paolo Ciliberti, Xavier Iriart, Giulia Tuo, Yogen Singh, Wendy Dewals, Constancio Medrano-Lopez, Amalia Tamariz-Martel, Carlo Pace Napoleone, Andrea Donti, Federico Gutierrez-Larraya, and Kristof Vandekerckhove
- Subjects
medicine.medical_specialty ,Ejection fraction ,biology ,business.industry ,030204 cardiovascular system & hematology ,medicine.disease ,Pericardial effusion ,Procalcitonin ,3. Good health ,Ferritin ,03 medical and health sciences ,0302 clinical medicine ,Troponin complex ,Intensive care ,Internal medicine ,Shock (circulatory) ,biology.protein ,medicine ,030212 general & internal medicine ,medicine.symptom ,10. No inequality ,business ,Cardiac imaging - Abstract
Background: The aim of the study was to document cardiovascular clinical findings, cardiac imaging and laboratory markers in children presenting with the novel multisystemic inflammatory syndrome associated with COVID-19. Methods: A real-time internet based survey was sent via the member mailing database for Association for European Paediatric and Congenital Cardiologists (AEPC) working groups for Cardiac Imaging and Cardiovascular Intensive Care member. Inclusion criteria was children 0-18 years admitted to hospital between March 1 and June 6, 2020 with diagnosis of an inflammatory syndrome and acute cardiovascular complications. Findings: A total of 286 children from 55 centres from 17 European countries were included. The median age was 8·4 years (IQR 3·8-12·4 years) and 67% were males. Most common cardiovascular complications were shock (40%), cardiac arrhythmias (35%), pericardial effusion (28%) and coronary artery dilatation (24%). Reduced left ventricular ejection fraction was present in 52% of patients and 93% had raised cardiac troponin (cTnT). The biochemical markers of inflammation were raised in majority of patients on admission: elevated CRP (99%), ferritin (79%), procalcitonin (96%), NT-proBNP (93%), IL-6 level (88%) and D-dimers (90%). There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and need of intensive care support (p
- Published
- 2020
31. Design of Electromagnetic Shielding Textiles Based on Industrial‐Grade Multiwalled Carbon Nanotubes and Graphene Nanoplatelets by Dip‐Pad‐Dry Process
- Author
-
Jose Morgado, Cristina Freire, Augusta Silva, Ana R. Sousa, Gilda Santos, Gleb N. Kakazei, Renata Matos, André Pereira, M. Fernando R. Pereira, O. Salomé G. P. Soares, Patrícia Soares, R. Vilarinho, S. A. Bunyaev, João Ferreira, Jose Barbosa, and Clara Pereira
- Subjects
Materials science ,Graphene ,Nanotechnology ,Surfaces and Interfaces ,Carbon nanotube ,Condensed Matter Physics ,Multiwalled carbon ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,law.invention ,Exfoliated graphite nano-platelets ,law ,Scientific method ,Electromagnetic shielding ,Materials Chemistry ,Electromagnetic interference shielding ,Electrical and Electronic Engineering - Published
- 2022
32. Pseudoaneurysm of the aortic arch early after coarctation repair in the neonatal period
- Author
-
José Pedro Neves, Ana Maria Teixeira, and Ana R Sousa
- Subjects
Aortic arch ,Heart Septal Defects, Ventricular ,Male ,medicine.medical_specialty ,Aorta, Thoracic ,030204 cardiovascular system & hematology ,Aortic Coarctation ,03 medical and health sciences ,Pseudoaneurysm ,0302 clinical medicine ,medicine.artery ,medicine ,Humans ,cardiovascular diseases ,Surgical repair ,Aortic Aneurysm, Thoracic ,business.industry ,Infant, Newborn ,General Medicine ,Aortic arch aneurysm ,Surgical correction ,Plastic Surgery Procedures ,medicine.disease ,Surgery ,030228 respiratory system ,Echocardiography ,Pediatrics, Perinatology and Child Health ,cardiovascular system ,Hypoplastic aortic arch ,Cardiology and Cardiovascular Medicine ,Complication ,business ,Tomography, X-Ray Computed ,Vascular Surgical Procedures ,Aneurysm, False - Abstract
Aortic arch aneurysm or pseudoaneurysm is a rare complication early after coarctation repair in the neonatal period. We report the case of a newborn with a ventricular septal defect and aortic coarctation with a hypoplastic aortic arch that developed a large aortic arch pseudoaneurysm following a radically extended end-to-end coarctation repair. Successful surgical correction of the pseudoaneurysm was performed.
- Published
- 2019
33. Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status
- Author
-
Ana R. Sousa, Anna Selby, Jeanette Bigler, Hans Bisgaard, J. Cunha, I.M. Adcock, A.C.C. Coelho, Ryan Santos Costa, Pieter-Paul Hekking, Louise Fleming, Kai Sun, Amphun Chaiboonchoe, C.V.N. Santana, P. Moura-Santos, Scott Wagers, Ratko Djukanovic, G.P. Pinheiro, G. Hedlin, J.V. de Jesus, Kian Fan Chung, Jacek Musiał, Thomas Geiser, F. Baribaud, Emília Maria Medeiros de Andrade Belitardo, L. Cardoso, Klaus Bønnelykke, Anthony D. Postle, P H Howarth, Adelmir Souza-Machado, Valmar Biao-Lima, Stephen J. Fowler, Craig E. Wheelock, Alvaro A. Cruz, Mauricio Lima Barreto, Maria Ilma Araujo, Massimo Caruso, Laurie Pahus, P. J. Cooper, Florian Singer, W.M.C. van Aalderen, Paulo Augusto Moreira Camargos, Wolfgang Seibold, Ildiko Horvath, René Lutter, P.C.A. Almeida, I. Pandis, Victoria M. Goss, Aruna T. Bansal, John H. Riley, M. Puig Valls, P. Powel, Amanda Roberts, Alexander Mazein, M. Miralpeix, I. Paixao-Araujo, B. De Meulder, Michael Boedigheimer, Isaac Suzart Gomes-Filho, Chris Compton, C. Auffray, Jamie Matthews, Diane Lefaudeux, Elena Formaggio, A.A. Cruz, L.M. Mello, Anthony V. D'Amico, A. Lima-Matos, J. Fernandes, P. J. Sterk, Clare S. Murray, Enrica Bucchioni, Andrea Meiser, D. Erzen, Roelinde Middelveld, M. van Geest, Jørgen Vestbo, Alan J. Knox, Graham Roberts, Norbert Krug, Stewart Bates, G. Santos-Lima, Maggie Davis, Stelios Pavlidis, Paul Skipp, Yike Guo, Ariane H. Wagener, E.V. Ponte, Jens M. Hohlfeld, A. Souza-Machado, M.A. Lessa, I.S. Muniz, C.S. Cruz, Nadja Hawwa Vissing, Neuza Maria Alcantara-Neves, Tim Higenbottam, Navin Rao, Dominic Burg, Sarah Masefield, Z. Weiszhart, Matthew J. Loza, J. Haughney, Simone Hashimoto, Per Bakke, B. Thornton, José Miguel Chatkin, Andrew Bush, SE Dahlen, Joost Brandsma, N. Mores, G. Praticò, Kathleen C. Barnes, Carolina Souza-Machado, Rafael Stelmach, V. Bião-Lima, Martina Gahlemann, Paolo Montuschi, T.M.O. Souza, V.S. Vasquez, Camila Alexandrina Figueiredo, P. Chanez, Eduardo Vieira Ponte, Neil Fitch, Anthony Rowe, Cecile T.J. Holweg, S.J. Wilson, K. Fichtner, Alexander Manta, Lidia Lins, Dominic E. Shaw, David Myles, Julie Corfield, B. Dahlén, Thomas Sandström, Peter J. Sterk, Ian M. Adcock, Ralf Sigmund, James P.R. Schofield, Urs Frey, Laura C. Rodrigues, Leila Denise Alves Ferreira Amorim, E.H.D. Bel, Anna James, R.A. Franco, Paula Cristina Andrade Almeida, Paul Brinkman, H. Ahmed, Veit J. Erpenbeck, Richard G. Knowles, National Institute for Health Research, Pulmonology, and AII - Inflammatory diseases
- Subjects
Male ,Cardiac & Cardiovascular Systems ,BLOOD ,Cross-sectional study ,COUNT ,Respiratory System ,Ethnic group ,Disease ,Severity of Illness Index ,Cohort Studies ,0302 clinical medicine ,Quality of life ,Forced Expiratory Volume ,Disease management ,Medicine ,030212 general & internal medicine ,610 Medicine & health ,1102 Cardiorespiratory Medicine and Haematology ,Middle Aged ,PREVALENCE ,Europe ,Phenotypes ,Phenotype ,INFECTIONS ,Female ,Life Sciences & Biomedicine ,Brazil ,Cohort study ,Pulmonary and Respiratory Medicine ,Adult ,Cross sectional study ,U-BIOPRED Study Groups ,03 medical and health sciences ,FEV1/FVC ratio ,ProAR Study Group ,Humans ,Socioeconomic status ,Asthma ,Science & Technology ,business.industry ,1103 Clinical Sciences ,medicine.disease ,SPIROMETRY ,REFERENCE VALUES ,respiratory tract diseases ,SEVERITY ,Cross-Sectional Studies ,030228 respiratory system ,Social Class ,Cardiovascular System & Cardiology ,Quality of Life ,business ,Biomarkers ,Demography - Abstract
Background Asthma prevalence is 339 million globally. ‘Severe asthma’ (SA) comprises subjects with uncontrolled asthma despite proper management. Objectives To compare asthma from diverse ethnicities and environments. Methods A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Results Among SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. Conclusions ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.
- Published
- 2019
34. Umeclidinium/Vilanterol Versus Tiotropium/Olodaterol in Maintenance-Naïve Patients with Moderate Symptomatic Chronic Obstructive Pulmonary Disease: A Post Hoc Analysis
- Author
-
Chris Compton, Ana R. Sousa, Gregory Feldman, Lee Tombs, David A. Lipson, Ian Naya, Isabelle Boucot, and Bernardino Alcázar Navarrete
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Combination therapy ,Long-acting β2-agonist ,medicine.drug_class ,Population ,LABA ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Maintenance therapy ,Respiratory Care ,Internal medicine ,Bronchodilator ,medicine ,COPD ,Umeclidinium ,Vilanterol ,030212 general & internal medicine ,education ,Original Research ,education.field_of_study ,business.industry ,Tiotropium ,Olodaterol ,LAMA ,medicine.disease ,Crossover study ,Long-acting muscarinic antagonist ,030228 respiratory system ,chemistry ,Maintenance-naïve ,business - Abstract
Introduction Appropriate timing for dual bronchodilator therapy initiation in chronic obstructive pulmonary disease (COPD) management is uncertain. Combination therapy is recommended as step-up from monotherapy or first-line treatment in patients with persistent symptoms. In this setting, umeclidinium/vilanterol (UMEC/VI) demonstrated improved lung function and reduced rescue medication use over tiotropium/olodaterol (TIO/OLO). This subgroup analysis explored efficacy differences between these combinations in patients naïve to COPD maintenance therapy before study entry. Methods Post hoc analysis of an 8-week, randomized, open-label, assessor-blind, two-period crossover study (204990; NCT02799784) comparing UMEC/VI 62.5/25 mcg and TIO/OLO 5/5 mcg, focused on maintenance-naïve (MN) patients with moderate COPD and persistent symptoms (modified Medical Research Council dyspnea score ≥ 2). Change from baseline (CFB) in trough forced expiratory volume in 1 s (FEV1), percentage of FEV1 responders (CFB ≥ 100 ml), rescue medication use and safety were evaluated. Results The MN population comprised 63% of the intent-to-treat (ITT) population (148/236 patients) and had similar baseline demographics. At week 8, adjusted mean (standard error) improvements in trough FEV1 from baseline were clinically meaningful for both combinations (UMEC/VI: 167 [17] ml; TIO/OLO 110 [18] ml; adjusted mean difference [95% confidence interval (CI)]: 57 [23–92] ml; p = 0.001; %CFB: 11 vs. 8%). Proportion of FEV1 responders was greater with UMEC/VI versus TIO/OLO at week 8 (60 vs. 42%; odds ratio [95% CI] 1.90 [1.12–3.22]; p = 0.018). Reduction in rescue medication use was 0.20 (95% CI 0.07–0.34) puffs/day greater with UMEC/VI versus TIO/OLO over weeks 1–8 (p = 0.003). Adverse events incidence was similar (UMEC/VI: 24%; TIO/OLO: 29%). Conclusions These results highlight that the efficacy difference between UMEC/VI and TIO/OLO demonstrated in the ITT population is maintained in MN patients. Greater lung function improvements with UMEC/VI versus TIO/OLO were accompanied by symptom improvements, as reflected in a significantly lower need for supplemental rescue medication. Funding GSK. Trial registration NCT02799784
- Published
- 2018
35. Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study
- Author
-
John H. Riley, Ian Naya, Neil Barnes, Lee Tombs, Ana R. Sousa, Bernardino Alcázar Navarrete, Sadhana Patel, Gregory J. Feldman, David A. Lipson, Chris Compton, [Feldman, Gregory J.] S Carolina Pharmaceut Res, Spartanburg, SC 29303 USA, [Sousa, Ana R.] GlaxoSmithKline, Resp Res & Dev, Stockley Pk West, Uxbridge, Middx, England, [Lipson, David A.] GlaxoSmithKline, Resp Res & Dev, King Of Prussia, PA USA, [Lipson, David A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA, [Tombs, Lee] Precise Approach Ltd, Birmingham, W Midlands, England, [Barnes, Neil] GlaxoSmithKline, Global Resp Franchise, Brentford, Middx, England, [Patel, Sadhana] GlaxoSmithKline, Global Resp Franchise, Brentford, Middx, England, [Compton, Chris] GlaxoSmithKline, Global Resp Franchise, Brentford, Middx, England, [Riley, John H.] GlaxoSmithKline, GlaxoSmithKline Med Res Ctr, Resp Therapy Area Unit, Stevenage, Herts, England, [Naya, Ian] GlaxoSmithKline, Resp Med, Brentford, Middx, England, [Alcazar Navarrete, Bernardino] Hosp Alta Resoluc Loja, Neumol, Granada, Spain, and GlaxoSmithKline
- Subjects
Male ,Quinuclidines ,Respimat ,Long-acting β2-agonist ,law.invention ,Pulmonary Disease, Chronic Obstructive ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,law ,Forced Expiratory Volume ,Medicine ,Pharmacology (medical) ,Vilanterol ,030212 general & internal medicine ,Original Research ,education.field_of_study ,COPD ,Cross-Over Studies ,Olodaterol ,LAMA ,Double-blind ,General Medicine ,Middle Aged ,Dry-powder inhaler ,Bronchodilator Agents ,Drug Combinations ,Treatment Outcome ,Anesthesia ,Combination ,Long-acting beta 2-agonist ,Female ,Bronchodilation ,Safety ,Moderate ,Population ,LABA ,Chlorobenzenes ,03 medical and health sciences ,Bronchodilators ,Double-Blind Method ,Administration, Inhalation ,Humans ,Umeclidinium ,Tiotropium Bromide ,education ,Benzyl Alcohols ,Dynamic hyperinflation ,Aged ,business.industry ,Nebulizers and Vaporizers ,Tiotropium ,medicine.disease ,Confidence interval ,Benzoxazines ,Long-acting muscarinic antagonist ,030228 respiratory system ,chemistry ,business - Abstract
Introduction We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD. Methods This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed. Results In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p
- Published
- 2017
36. Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation
- Author
-
Roberta Milone, Hilary Marshall, F A Symon, Andrew J. Wardlaw, Beverley Hargadon, S J Bolton, Peter A. Chalk, Christopher E. Brightling, Matthew Richardson, Linda C. Warnock, Annette T. Hastie, Richard G. Knowles, Ana R. Sousa, Richard P. Marshall, Reynold A. Panettieri, Eugene R. Bleecker, Pranab Haldar, and Rick Williamson
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.drug_class ,Prednisolone ,Immunology ,Administration, Oral ,Nitric Oxide ,Severity of Illness Index ,Anti-asthmatic Agent ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Adrenal Cortex Hormones ,Severity of illness ,Eosinophilic ,medicine ,Humans ,Immunology and Allergy ,Clinical significance ,Anti-Asthmatic Agents ,Young adult ,Asthma ,business.industry ,Middle Aged ,respiratory system ,medicine.disease ,Respiratory Function Tests ,respiratory tract diseases ,Eosinophils ,Treatment Outcome ,030104 developmental biology ,030228 respiratory system ,Exhalation ,Cytokines ,Corticosteroid ,Female ,business ,Biomarkers ,medicine.drug - Abstract
Background Patients with severe asthma appear relatively corticosteroid resistant. Corticosteroid responsiveness is closely related to the degree of eosinophilic airway inflammation. The extent to which eosinophilic airway inflammation in severe asthma responds to treatment with systemic corticosteroids is not clear. Objective To relate the physiological and inflammatory response to systemic corticosteroids in asthma to disease severity and the baseline extent of eosinophilic inflammation. Methods Patients with mild/moderate and severe asthma were investigated before and after two-weeks of oral prednisolone (Clintrials. gov NCT00331058 and NCT00327197). We pooled the results from 2 studies with common protocols. The US study contained 2 independent centres and the UK 1 independent centre. The effect of oral corticosteroids on FEV1, Pc20, airway inflammation and serum cytokines were investigated. Baseline measurements were compared with healthy subjects. Results 32 mild/moderate asthmatics, 50 severe asthmatics and 35 healthy subjects took part. At baseline both groups of asthmatics had a lower FEV1 and Pc20 and increased eosinophilic inflammation compared to healthy subjects. The severe group had a lower FEV1 and more eosinophilic inflammation compared to mild/moderate asthmatics. Oral prednisolone caused a similar degree of suppression of eosinophilic inflammation in all compartments in both groups of asthmatics. There were small improvements in FEV1 and Pc20 for both mild/ moderate and severe asthmatics with a correlation between the baseline eosinophilic inflammation and the change in FEV1. There was a ~50% reduction in the serum concentration of CXCL10 (IP-10), CCL22 (MDC), CCL17 (TARC), CCL-2 (MCP-1) and CCL-13 (MCP-4) in both asthma groups after oral corticosteroids. Conclusions and Clinical Relevance Disease severity does not influence the response to systemic corticosteroids. The study does not therefore support the concept that severe asthma is associated with corticosteroid resistance. Only baseline eosinophilic inflammation was associated with the physiological response to corticosteroids, confirming the importance of measuring eosinophilic inflammation to guide corticosteroid use. This article is protected by copyright. All rights reserved.
- Published
- 2017
37. Subtypes of eosinophilic asthma with discrete gene pathway phenotypes
- Author
-
Kian Fan Chung, Ben Nicholas, Norbert Krug, Peter J. Sterk, Ian M. Adcock, James P.R. Schofield, Ana R. Sousa, Thomas Sandström, Susan J. Wilson, Fabio Strazzeri, René Lutter, Massimo Caruso, Peter H. Howarth, Aruna T. Bansal, Jeanne-Marie Perotin-Collard, Stephen J. Fowler, Per Bakke, Ildiko Horvath, Diane Lefaudeux, John H. Riley, Paolo Montuschi, Joost Brandsma, Kai Sun, Bertrand De Meulder, Dominick E. Shaw, Paul Skipp, Yike Guo, Sven-Erik Dahlén, Charles Auffray, Xian Yang, Ioannis Pandis, Julie Corfield, Anthony Rowe, Jonathan Ward, Ratko Djukanovic, Marek Sanak, and Commission of the European Communities
- Subjects
Science & Technology ,business.industry ,Respiratory System ,Eosinophilic asthma ,Genomics ,respiratory system ,Eosinophil ,medicine.disease ,Phenotype ,Asthma ,respiratory tract diseases ,medicine.anatomical_structure ,immune system diseases ,Immunology ,Medicine ,Adults ,Respiratory system ,business ,Life Sciences & Biomedicine ,11 Medical and Health Sciences ,Gene pathway - Abstract
Background: Blood eosinophil counts ≥0.3x109/L are used to define Type-2, eosinophilic asthma. However, differential responses to T2 biologics of patients with eosinophilic asthma suggests that thi ...
- Published
- 2019
38. Understanding the Patient Experience of Severe, Recurrent, Bilateral Nasal Polyps: A Qualitative Interview Study in the United States and Germany
- Author
-
Ana R. Sousa, Linda Nelsen, Robert Chan, Helena Bradley, Robyn von Maltzahn, Adam Gater, R. Hall, C. Trennery, and Mirko V Sikirica
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Activities of daily living ,Catarrh ,Nasal congestion ,Interviews as Topic ,03 medical and health sciences ,0302 clinical medicine ,Nasal Polyps ,Quality of life ,Recurrence ,Germany ,Patient experience ,Activities of Daily Living ,medicine ,Humans ,Nasal polyps ,030212 general & internal medicine ,Sinusitis ,Nose ,Qualitative Research ,Rhinitis ,business.industry ,030503 health policy & services ,Health Policy ,Public Health, Environmental and Occupational Health ,Middle Aged ,medicine.disease ,United States ,medicine.anatomical_structure ,Quality of Life ,Female ,Steroids ,medicine.symptom ,0305 other medical science ,business ,Qualitative research - Abstract
Objectives To qualitatively explore patient experiences of severe, recurrent, bilateral nasal polyps (NP). Methods A targeted literature review of published qualitative studies and online blogs describing patient experiences of NP was conducted. Semistructured concept elicitation interviews were conducted in the United States and Germany with participants ≥18 years with severe, recurrent, bilateral NP to explore their symptom experience and impacts on health-related quality of life (HRQoL; NCT03221192 ). A subset of 10 participants reported symptoms and impacts using a smartphone or tablet application (app) over a 10-day period. Results A paucity of qualitative evidence regarding patient experience of NP was identified from the literature or blog review. Twenty-seven participant interviews were conducted. Thirty-six symptoms were identified, including 7 primary symptoms (nasal congestion [n = 27 of 27], breathing difficulties [n = 27 of 27], postnasal drip [n = 25 of 27], runny nose [n = 24 of 27], head/facial pressure [n = 23 of 27], loss of smell [n = 23 of 27], loss of taste [n = 22 of 27]) and 29 secondary symptoms (the most common were mucus/catarrh and nose bleeds [both n = 20 of 27]). Most symptoms were reported to vary both within and between days. Sixty impacts of severe NP were reported, including impacts on sleep (n = 22 of 27), physical functioning (n = 21 of 27), activities of daily living (n = 21 of 27), emotional well-being (n = 27 of 27), treatment (n = 23 of 27), social life (n = 26 of 27), and work (n = 19 of 27). Symptoms/impacts reported using the app were consistent with interview findings, although new symptoms were identified (ear pain, throat pain, nasal scabs, and nasal burning). These results supported the development of a conceptual model outlining concepts related to symptoms, impacts, and treatment of NP. Conclusions Severe, recurrent, bilateral NP are associated with a range of symptoms that have significant detrimental impact on HRQoL.
- Published
- 2019
39. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
- Author
-
Zala Jevnikar, Jörgen Östling, Elisabeth Ax, Jenny Calvén, Kristofer Thörn, Elisabeth Israelsson, Lisa Öberg, Akul Singhania, Laurie C.K. Lau, Susan J. Wilson, Jonathan A. Ward, Anoop Chauhan, Ana R. Sousa, Bertrand De Meulder, Matthew J. Loza, Frédéric Baribaud, Peter J. Sterk, Kian Fan Chung, Kai Sun, Yike Guo, Ian M. Adcock, Debbie Payne, Barbro Dahlen, Pascal Chanez, Dominick E. Shaw, Norbert Krug, Jens M. Hohlfeld, Thomas Sandström, Ratko Djukanovic, Anna James, Timothy S.C. Hinks, Peter H. Howarth, Outi Vaarala, Marleen van Geest, Henric Olsson, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, F.K. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, A.J. James, R. Knowles, A.J. Knox, N. Krug, D. Lefaudeux, M.J. Loza, A. Manta, J.G. Matthews, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, P. Montuschi, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, A. Postle, P. Powel, G. Praticò, N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J.P.R. Schofield, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson, Publica, HUS Children and Adolescents, Commission of the European Communities, Pulmonology, AII - Inflammatory diseases, and Paediatric Pulmonology
- Subjects
Male ,0301 basic medicine ,MMP3 ,Allergy ,MATRIX METALLOPROTEINASES ,Respiratory Medicine and Allergy ,Eepithelial integrity ,airway inflammation ,Systemic inflammation ,DISEASE ,Cohort Studies ,transcriptomics ,0302 clinical medicine ,Receptors ,Immunology and Allergy ,Lung ,Macrophage inflammatory protein ,Cells, Cultured ,Lungmedicin och allergi ,remodeling ,Toll-like receptor ,Cultured ,CHITINASE-LIKE PROTEIN ,3. Good health ,Phenotype ,TARGET ,medicine.anatomical_structure ,1107 Immunology ,Airway Remodeling ,eosinophils ,medicine.symptom ,Life Sciences & Biomedicine ,hierarchical clustering ,Signal Transduction ,Adult ,Settore BIO/14 - FARMACOLOGIA ,Immunology ,lung epithelium ,03 medical and health sciences ,HYPERRESPONSIVENESS ,Respiratory Hypersensitivity ,medicine ,Humans ,Hierarchical Clustering ,Inflammation ,Science & Technology ,Innate immune system ,exacerbation frequency ,Interleukin-6 ,business.industry ,Sputum ,Epithelial Cells ,Gene signature ,Receptors, Interleukin-6 ,DYSFUNCTION ,Asthma ,respiratory tract diseases ,Eosinophils ,Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group ,Cross-Sectional Studies ,SEVERITY ,030104 developmental biology ,Gene Expression Regulation ,030228 respiratory system ,INTERLEUKIN-6 RECEPTOR ,BARRIER FUNCTION ,3121 General medicine, internal medicine and other clinical medicine ,CELLS ,epithelial integrity ,IL-6 signaling ,Exacerbation frequency ,Transcriptome ,business ,Biomarkers - Abstract
BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
- Published
- 2019
40. Morse-clustering of a Topological Data Analysis Network Identifies Phenotypes of Asthma Based on Blood Gene Expression Profiles
- Author
-
Ben D. MacArthur, Ioannis Pandis, Ramanan D, Fabio Strazzeri, Paul Skipp, P. J. Sterk, K.F. Chung, John H. Riley, Jeanette Bigler, Aruna T. Bansal, Richard G. Knowles, Diane Lefaudeux, Craig E. Wheelock, Sven-Erik Dahlén, Charles Auffray, Rubén J. Sánchez-García, Schofield Jpr, Michael Boedigheimer, Ratko Djukanovic, Rob M. Ewing, I.M. Adcock, Kaiyuan Sun, De Meulder B, and Ana R. Sousa
- Subjects
Untranslated region ,0303 health sciences ,Microarray ,Discrete Morse theory ,Computational biology ,Biology ,Phenotype ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Glucocorticoid receptor ,030228 respiratory system ,Gene expression ,Topological data analysis ,Cluster analysis ,030304 developmental biology - Abstract
Stratified medicine requires discretisation of disease populations for targeted treatments. We have developed and applied a discrete Morse theory clustering algorithm to a Topological Data Analysis (TDA) network model of 498 gene expression profiles of peripheral blood from asthma and healthy participants. The Morse clustering algorithm defined nine clusters, BC1-9, representing molecular phenotypes with discrete phenotypes including Type-1, 2 & 17 cytokine inflammatory pathways. The TDA network model and clusters were also characterised by activity of glucocorticoid receptor signalling associated with different expression profiles of glucocorticoid receptor (GR), according to microarray probesets targeted to the start or end of the GR mRNA’s 3’ UTR; suggesting differential GR mRNA processing as a possible driver of asthma phenotypes including steroid insensitivity.
- Published
- 2019
41. IL-17-high asthma with features of a psoriasis immunophenotype
- Author
-
Jörgen Östling, Marleen van Geest, James P.R. Schofield, Zala Jevnikar, Susan Wilson, Jonathan Ward, Rene Lutter, Dominick E. Shaw, Per S. Bakke, Massimo Caruso, Sven-Erik Dahlen, Stephen J. Fowler, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Thomas Sandström, Kai Sun, Ioannis Pandis, Charles Auffray, Ana R. Sousa, Yike Guo, Ian M. Adcock, Peter Howarth, Kian Fan Chung, Jeanette Bigler, Peter J. Sterk, Paul J. Skipp, Ratko Djukanović, Outi Vaarala, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, K.F. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, Y. Guo, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, P. Howarth, A.J. James, R. Knowles, A.J. Knox, N. Krug, D. Lefaudeux, M.J. Loza, R. Lutter, A. Manta, S. Masefield, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, P. Montuschi, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, P. Powell, G. Praticò, M. Puig N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson, Antonios Aliprantis, David Allen, Kjell Alving, P. Badorrek, David Balgoma, S. Ballereau, Clair Barber, Manohara Kanangana Batuwitage, A. Bautmans, A. Bedding, A.F. Behndig, Jorge Beleta, A. Berglind, A. Berton, Grazyna Bochenek, Armin Braun, D. Campagna, Leon Carayannopoulos, C. Casaulta, Romanas Chaleckis, B. Dahlén, imothy Davison, Jorge De Alba, Inge De Lepeleire, Tamara Dekker, Ingrid Delin, P. Dennison, Annemiek Dijkhuis, Paul Dodson, Aleksandra Draper, K. Dyson, Jessica Edwards, L. El Hadjam, Rosalia Emma, Magnus Ericsson, C. Faulenbach, Breda Flood, G. Galffy, Hector Gallart, D. Garissi, J. Gent, M. Gerhardsson de Verdier, D. Gibeon, Cristina Gomez, Kerry Gove, Neil Gozzard, E. Guillmant-Farry, E. Henriksson, Lorraine Hewitt, U. Hoda, Richard Hu, Sile Hu, X. Hu, E. Jeyasingham, K. Johnson, N. Jullian, Juliette Kamphuis, Erika J. Kennington, Dyson Kerry, G. Kerry, M. Klüglich, Hugo Knobel, Johan Kolmert, J.R. Konradsen, Maxim Kots, Kosmas Kretsos, L. Krueger, Scott Kuo, Maciej Kupczyk, Bart Lambrecht, A.-S. Lantz, Christopher Larminie, L.X. Larsson, P. Latzin, N. Lazarinis, N. Lemonnier, Saeeda Lone-Latif, L.A. Lowe, Alexander Manta, Lisa Marouzet, Jane Martin, Caroline Mathon, L. McEvoy, Sally Meah, A. Menzies-Gow, Leanne Metcalf, Maria Mikus, Philip Monk, Shama Naz, K. Nething, Ben Nicholas, U. Nihlén, Peter Nilsson, R. Niven, B. Nordlund, S. Nsubuga, Antonio Pacino, Susanna Palkonen, J. Pellet, Giorgio Pennazza, Anne Petrén, Sandy Pink, C. Pison, Anthony Postle, Malayka Rahman-Amin, Lara Ravanetti, Emma Ray, Stacey Reinke, Leanne Reynolds, K. Riemann, Martine Robberechts, J.P. Rocha, C. Rossios, Kirsty Russell, Michael Rutgers, G. Santini, Marco Santoninco, M. Saqi, Corinna Schoelch, S. Scott, N. Sehgal, Marcus Sjödin, Barbara Smids, Caroline Smith, Jessica Smith, Katherine M. Smith, P. Söderman, A. Sogbessan, F. Spycher, Doroteya Staykova, S. Stephan, J. Stokholm, K. Strandberg, M. Sunther, M. Szentkereszty, L. Tamasi, K. Tariq, John-Olof Thörngren, Jonathan Thorsen, S. Valente, Marianne van de Pol, C.M. van Drunen, Jonathan Van Eyll, Jenny Versnel, Anton Vink, C. von Garnier, A. Vyas, Frans Wald, Samantha Walker, Kristiane Wetzel, Coen Wiegman, Siân Williams, Xian Yang, Elizabeth Yeyasingham, W. Yu Amgen, W. Zetterquist, Z. Zolkipli, A.H. Zwinderman, Publica, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Pulmonology, AII - Inflammatory diseases, Experimental Immunology, Ear, Nose and Throat, Epidemiology and Data Science, APH - Methodology, and Commission of the European Communities
- Subjects
0301 basic medicine ,Male ,URINARY-EXCRETION ,Allergy ,Neutrophils ,Inflammatory bowel disease ,Cohort Studies ,DOUBLE-BLIND ,0302 clinical medicine ,Immunology and Allergy ,POPULATION ,Interleukin-13 ,Interleukin-17 ,psoriasis ,BRODALUMAB ,Up-Regulation ,IL-17 ,Phenotype ,1107 Immunology ,Biomarker (medicine) ,Female ,Interleukin 17 ,medicine.symptom ,Life Sciences & Biomedicine ,ENDOTYPES ,Signal Transduction ,EXPRESSION ,Adult ,Settore BIO/14 - FARMACOLOGIA ,Immunology ,PHENOTYPES ,Bronchi ,03 medical and health sciences ,INFLAMMATION ,Psoriasis ,medicine ,Humans ,Interleukin 8 ,Asthma ,U-BIOPRED Study Group ,Science & Technology ,business.industry ,Gene Expression Profiling ,biomarkers ,Epithelial Cells ,asthma ,bronchial brushings ,medicine.disease ,bronchial biopsies ,Neutrophilia ,030104 developmental biology ,030228 respiratory system ,EXACERBATION ,CELLS ,Sputum ,business ,Transcriptome ,Biomarkers - Abstract
Background The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
- Published
- 2019
42. P503 MEPOLIZUMAB FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPS: COMORBID ASTHMA, NSAID EXACERBATED RESPIRATORY DISEASE, EOSINOPHIL STRATIFICATION
- Author
-
Ana R. Sousa, Han Jinbo, Claus Bachert, O. Kante, C. Hopkins, R. Schlosser, Jorge Maspero, A. Chaker, L. Sowerby, and D. Karidi-Andrioti
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Chronic rhinosinusitis ,business.industry ,Immunology ,Respiratory disease ,Eosinophil ,medicine.disease ,Gastroenterology ,Stratification (mathematics) ,medicine.anatomical_structure ,Internal medicine ,medicine ,Immunology and Allergy ,Nasal polyps ,business ,Mepolizumab ,medicine.drug ,Asthma - Published
- 2020
43. Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study
- Author
-
Aruna T. Bansal, Matthew J. Loza, Dominick E. Shaw, Neil Fitch, Diane Lefaudeux, Barbro Dahlén, David Gibeon, Kian Fan Chung, Charles Auffray, Peter H. Howarth, Susan J. Wilson, Ana R. Sousa, Norbert Krug, Yike Guo, Peter J. Sterk, Ian M. Adcock, Pascal Chanez, Kai Sun, Bertrand De Meulder, Julie Corfield, Jonathan Ward, Ratko Djukanovic, Frédéric Baribaud, Thomas Sandström, Jens M. Hohlfeld, Commission of the European Communities, National Institute for Health Research, Publica, Amsterdam institute for Infection and Immunity, and Pulmonology
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Biopsy ,Respiratory System ,Acrylic Resins ,airway inflammation ,Bronchial brushing ,0302 clinical medicine ,Submucosa ,Immunopathology ,Oligonucleotide Array Sequence Analysis ,medicine.diagnostic_test ,Immunochemistry ,cigarette smoke ,Smoking ,11 Medical And Health Sciences ,Middle Aged ,Europe ,Phenotype ,medicine.anatomical_structure ,Methacrylates ,Female ,medicine.symptom ,Adult ,Pulmonary and Respiratory Medicine ,Bronchi ,Inflammation ,03 medical and health sciences ,Bronchoscopy ,expression ,medicine ,Humans ,TRPM1 ,Asthma ,research ,business.industry ,Bronchial-mucosa ,Case-control study ,cell ,medicine.disease ,Cross-Sectional Studies ,030104 developmental biology ,030228 respiratory system ,Case-Control Studies ,Immunology ,exhaled nitric oxide ,Fluticasone ,Transcriptome ,business - Abstract
The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild–moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups.In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm−2) compared with both severe asthma groups (SAn: 17.4 mm−2, p−2, p=0.01) and with the MMA group (21.2 mm−2, p=0.01). The number of CD4+lymphocytes was decreased in the SAs/ex group (4.7 mm−2) compared with the SAn (11.6 mm−2, p=0.002), MMA (10.1 mm−2, p=0.008) and HC (10.6 mm−2, pAffymetrix microarray analysis identified seven probe sets in the bronchial brushing samples that had a positive relationship with submucosal eosinophils. These mapped toCOX-2(cyclo-oxygenase-2),ADAM-7(disintegrin and metalloproteinase domain-containing protein 7),SLCO1A2(solute carrier organic anion transporter family member 1A2),TMEFF2(transmembrane protein with epidermal growth factor like and two follistatin like domains 2) andTRPM-1(transient receptor potential cation channel subfamily M member 1); the remaining two are unnamed.We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.
- Published
- 2016
44. Nasal Polyp Symptoms: How Well Do Physicians Know Their Patients?
- Author
-
Shibing Yang, Megan Scott, Mark Small, Robert Chan, Ana R. Sousa, Victoria S Benson, and Gary Milligan
- Subjects
Immunology ,Immunology and Allergy - Published
- 2020
45. 'T2-high' in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin
- Author
-
Francois Ng Kee Kwong, Bertrand De Meulder, Julie Corfield, Peter J. Sterk, Uruj Hoda, Ian M. Adcock, Pascal Chanez, F. Baribaud, Ana R. Sousa, Kai Sun, Steve J. Fowler, Matthew J. Loza, Richard G. Knowles, Louise Fleming, Stelios Pavlidis, Kian Fan Chung, Kentaro Takahashi, Jiaxing Xie, Yike Guo, V. Elyasigomari, Peter H. Howarth, Paul-Michael Agapow, Charles Auffray, Dominic E. Shaw, Ratko Djukanovic, Commission of the European Communities, AII - Inflammatory diseases, and Pulmonology
- Subjects
Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lydia Becker Institute ,Respiratory System ,Periostin ,Nitric Oxide ,Leukocyte Count ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,on behalf of the U-BIOPRED Study Group ,ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation ,Eosinophilia ,medicine ,Humans ,Prospective Studies ,Respiratory system ,Asthma ,business.industry ,Interleukins ,Smoking ,Sputum ,Interleukin ,11 Medical And Health Sciences ,Immunoglobulin E ,Middle Aged ,Eosinophil ,respiratory system ,medicine.disease ,respiratory tract diseases ,Eosinophils ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Breath Tests ,030228 respiratory system ,Case-Control Studies ,Exhaled nitric oxide ,Immunology ,Female ,medicine.symptom ,business ,Cell Adhesion Molecules ,Biomarkers - Abstract
Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild–moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort.The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs.37% of asthmatics (45% nonsmoking severe asthma, n=49; 33% of smoking or ex-smoking severe asthma, n=18; and 28% mild–moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher exhaled nitric oxide fraction (FeNO) and blood and sputum eosinophils, but not serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. FeNO (≥30 ppb) and blood eosinophils (≥300 cells·µL−1) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression.T2-high severe asthma can be predicted to some extent from raised levels of FeNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.
- Published
- 2018
46. Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort
- Author
-
Barbro Dahlén, Ioannis Pandis, Julie Corfield, Charles Auffray, Norbert Krug, Peter H. Howarth, Ildiko Horvath, Per Bakke, Rosalia Emma, Lorena Fabbella, Kian Fan Chung, Paolo Montuschi, Massimo Caruso, Aruna T. Bansal, Diane Lefaudeux, Ratko Djukanovic, Thomas Sandström, Louise Fleming, Ana R. Sousa, Marek Sanak, Peter J. Sterk, Ian M. Adcock, Pascal Chanez, Swen-Erik Dahlen, René Lutter, Stephen J. Fowler, Craig E. Wheelock, Johan Kolmert, Florian Singer, Matthew J. Loza, Dominick E. Shaw, Bertrand De Meulder, Loukides, Stelios, Publica, Pulmonology, and AII - Inflammatory diseases
- Subjects
Male ,0301 basic medicine ,REDOX REGULATION ,RAT LUNG ,Pulmonology ,Physiology ,Respiratory Medicine and Allergy ,NF-KAPPA-B ,lcsh:Medicine ,Urine ,Pathology and Laboratory Medicine ,Biochemistry ,Gastroenterology ,Bronchial brushing ,AIRWAY DISEASES ,Cohort Studies ,Habits ,chemistry.chemical_compound ,Medicine and Health Sciences ,Smoking Habits ,SUPEROXIDE-DISMUTASE ,oxidative stress ,Public and Occupational Health ,lcsh:Science ,Immune Response ,Lungmedicin och allergi ,Multidisciplinary ,Smoking ,General Medicine ,Middle Aged ,Body Fluids ,Enzymes ,3. Good health ,Multidisciplinary Sciences ,Dismutases ,Cohort ,Science & Technology - Other Topics ,Biomarker (medicine) ,Female ,Anatomy ,medicine.symptom ,General Agricultural and Biological Sciences ,Research Article ,Adult ,severe asthma ,medicine.medical_specialty ,Settore BIO/14 - FARMACOLOGIA ,Substance-Related Disorders ,General Science & Technology ,Urinary system ,Immunology ,PATHOPHYSIOLOGY ,610 Medicine & health ,General Biochemistry, Genetics and Molecular Biology ,MECHANISMS ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,Internal medicine ,Mental Health and Psychiatry ,Bronchoscopy ,MD Multidisciplinary ,isoprostanes ,Tobacco Smoking ,medicine ,Humans ,U-BIOPRED Study Group ,Asthma ,Inflammation ,Behavior ,Creatinine ,Science & Technology ,NITRIC-OXIDE ,Superoxide Dismutase ,business.industry ,lcsh:R ,Sputum ,LUNG INFLAMMATION ,Biology and Life Sciences ,Smoking Related Disorders ,Proteins ,Cell Biology ,medicine.disease ,respiratory tract diseases ,Mucus ,030104 developmental biology ,chemistry ,CIGARETTE-SMOKE ,Enzymology ,lcsh:Q ,business ,Biomarkers - Abstract
Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF2α; IS-transcriptomics; BB-transcriptomics; BBr-transcriptomics). Urinary 8-iso-PGF2α was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF2α was increased in SAs/ex, median (IQR) = 31.7 (24.5-44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6-36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4-47.7), vs. ESA, median (IQR) = 29.4 (22.3-40.5), and NSA, median (IQR) = 26.5 (19.6-16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF2α in the smokers/ex-smokers group. Trial registration ClinicalTrials.gov-Identifier: NCT01976767.
- Published
- 2018
47. Late Breaking Abstract - Longitudinal analysis of variation in clinical features from the U-BIOPRED severe asthma cohort
- Author
-
Julie Corfield, Björn Nordlund, Andrew Bush, Ratko Djukanovic, John H. Riley, G. Hedlin, Ana R. Sousa, Dominick E. Shaw, Claire Murray, Florian Singer, Stewart Bates, Wen Yu, Stephen J. Fowler, Scott Wagers, Peter J. Sterk, Ian M. Adcock, Urs Frey, Simone Hashimoto, Michael Boedigheimer, Graham Roberts, Xuguang Hu, Charles Auffray, Wim M. C. van Aalderen, Kian Fan Chung, Klaus Bønnelykke, Jeanette Bigler, Hans Bisgaard, Aruna T. Bansal, Louise Fleming, and Stelios Pavlidis
- Subjects
Pediatrics ,medicine.medical_specialty ,Exacerbation ,business.industry ,Severe asthma ,Disease progression ,Disease ,respiratory tract diseases ,Asthma Control Questionnaire ,Cohort ,Biomarker (medicine) ,Medicine ,business ,Lung function - Abstract
Introduction: The U-BIOPRED cohort presents an exceptional opportunity to longitudinally monitor disease variation in severe asthma. Aims: To determine the variability of severe asthma over 12-24 months in the U-BIOPRED cohort by initially focusing on clinical parameters; lung function, exacerbations and asthma symptom control. Methods: Lung function, exacerbation history and asthma control questionnaire (ACQ-5) were determined at baseline (Shaw et al.) and longitudinally. Results: 321 severe asthma patients were present in the longitudinal cohort with a mean of 454 days in the study. The longitudinal set of participants (321) were a good representation of the whole of severe asthma cohort at baseline (421). Most clinical and biomarker measurements including the FEV1 actual, exacerbation and ACQ means were not significantly different between the baseline and longitudinal visits- Table 1. There was no difference between the smoking and non-smoking cohorts. However at an individual level there was variation and some participants deteriorated, and some improved. Summary: Longitudinal U-BIOPRED data quality is valid. Further methods of analysis will move away from characterisation of group means towards understanding individual factors relating to disease progression in the U-BIOPRED cohort.
- Published
- 2018
48. Further resolution of non-T2 asthma subtypes from high-throughput sputum transciptomics data in U-BIOPRED
- Author
-
Nazanin Zounemat Kermani, Matthew J. Loza, Stelios Pavlidis, Chih-Hsi Kuo, Ratko Djukanovic, Ana R. Sousa, Yike Guo, Frédéric Baribaud, Fan Chung, Anthony Rowe, Mansoor Saqi, Paul-Michael Agapow, Bertrand De Meulder, Louise Fleming, Peter J. Sterk, Ian M. Adcock, Diane Lefaudeux, Charles Auffray, Julie Corfield, Richard G. Knowles, and Commission of the European Communities
- Subjects
Science & Technology ,business.industry ,Respiratory System ,Inflammasome ,medicine.disease ,Neutrophilia ,TAC1 ,Immunology ,Gene expression ,medicine ,Eosinophilia ,Sputum ,medicine.symptom ,business ,Life Sciences & Biomedicine ,Gene ,11 Medical and Health Sciences ,medicine.drug ,Asthma - Abstract
Background: Precision medicine of asthma requires understanding of its heterogeneity and molecular pathophysiology. Aim: Three sputum-derived transcriptomic clusters (TACs) were previously identified [Kuo at al. Eur Respir J.2017, 49] in the U-BIOPRED cohort: TAC1 consisting of T2 high patients with eosinophilia, TAC2 with neutrophilia and inflammasome activation and TAC3, a more heterogeneous cluster with mostly paucigranulocytic patients. We further refine TAC3. Methods: Gaussian mixture modelling for model-based clustering was applied to sputum gene expression of 104 asthmatic participants from the adult cohort to substructure TAC3. Gene set variation analysis (GSVA) was used to explore the enrichment of gene signatures across the TACs. Results: We again produce the three TACs (TAC1 N=23, TAC2 N=24) but TAC3 was further split into two groups (TAC3a N=28, TAC3b N=29), distinguished by distinct neutrophils and macrophages density and enrichment of IL13 stimulation, inflammasome activation and OXPHOS gene signatures (Figure), as well as IL-4 and LPS-stimulated macrophage gene signatures. However, there were no distinguishing clinical features. Conclusion: Identification of sub-structure of sputum TACs, particularly of TAC3, will help towards improved targeted therapies.
- Published
- 2018
49. Unsupervised and externally validated clinical cluster analysis from the U-BIOPRED paediatric cohorts
- Author
-
Elisabeth H. Bel, Anna Selby, Ratko Djukanovic, Andrew Bush, Gunilla Hedlin, Urs Frey, Dominic E. Shaw, Bertrand De Meulder, Gianluca Praticò, Hans Bisgaard, Stephen J. Fowler, Paul Brinkman, Graham Roberts, I. Pandis, Aruna T. Bansal, Louise Fleming, Kian Fan Chung, Wim M. C. van Aalderen, Susanne J. H. Vijverberg, Simone Hashimoto, Clare S. Murray, Diane Lefaudeux, Julie Corfield, Björn Nordlund, Ana R. Sousa, Anthony Rowe, Nadja Hawwa Vissing, Charles Auffray, Anke-Hilse Maitland-van der Zee, Florian Singer, Scott Wagers, Zaraquiza Zolkipli, Marta Puig Valls, and Peter J. Sterk
- Subjects
Cart ,medicine.medical_specialty ,Stability test ,Quality of life ,business.industry ,Internal medicine ,Cohort ,Medicine ,Medical history ,Clinical significance ,Disease ,business ,Cluster analysis - Abstract
Rationale: Paediatric severe asthma is a heterogeneous disease suggesting that there may be discrete underlying clinical phenotypes. Objective: To generate and validate unbiased paediatric clusters in U-BIOPRED. Methods: Cross-sectional analysis of baseline data from the European U-BIOPRED study. Demography, medical history, medication, environmental risk factors, asthma control and quality of life data were collected. External validation utilised a Dutch community paediatric-asthma cohort (PACMAN). Clinical variables were first condensed by factor analysis, followed by subsampled (10000x, proportion: 90%) partition-around-medoid clustering and stability testing by consensus distributions and Calinski & Harabasz index. Finally Classification and Regression Tree Analysis (CART) was applied to generate a prediction model. Results: 250 patients (147 male, 7.9 ±4.8 yrs) with a complete data set of 34 clinical variables were included generating 7 stable clusters (figure) with unique clinical characteristics. Clustering of the PACMAN cohort using the same variables and application of CART-model delivered 3 phenotypes, in agreement with the U-BIOPRED less severe phenotypes (P2,P3,P6). Conclusion: Unsupervised analysis based on clinical parameters revealed 7 stable clusters of paediatric asthma. Part of these clusters could be replicated in an external cohort, suggesting broad pathophysiological and clinical relevance.
- Published
- 2018
50. Weighted Gene Co-expression Network Analysis of blood paediatric samples from the U-BIOPRED study identifies oxidative stress association with asthma severity
- Author
-
John H. Riley, Charles Auffray, Simone Hashimoto, Bertrand De Meulder, Yike Guo, Kai Sun, Ratko Djukanovic, Graham Roberts, Frédéric Baribaud, Adam Taylor, Karen Affleck, Fan Chung, I. Pandis, Louise Fleming, Matthew J. Loza, Peter J. Sterk, Julie Corfield, Stelios Pavlidis, Ian M. Adcock, Anthony Rowe, Richard G. Knowles, James P.R. Schofield, and Ana R. Sousa
- Subjects
business.industry ,Asthma severity ,Gene regulatory network ,medicine.disease ,medicine.disease_cause ,Phenotype ,Immunology ,Gene expression ,medicine ,Gene co-expression network ,business ,Gene ,Oxidative stress ,Asthma - Abstract
Background: Many children with asthma exhibit uncontrolled symptoms despite inhaled corticosteroid therapy. The molecular pathways linked to this phenotype are unknown. Aim: To investigate gene expression in paediatric severe and moderate/mild asthma blood samples. Methods: Gene expression analysis was applied on severe and mild asthma samples from pre- and school-age children (SApre,N=62; MApre,N=42; SAsc,N=75 and MAsc,N=37). Gene network analysis (WGCNA) was applied separately on the pre- and school-age data. Obtained gene modules were compared with the Jaccard Index. Results: No genes weresignificantly differentially-expressed in SA versus MA asthma in the two age groups (FDR Conclusion: WGCNA implicates mitochondrial oxidative stress in early onset severe asthma that needs further investigation.
- Published
- 2018
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.