Author: "Philippe Reix" / Topic: cystic fibrosis - Searchworks@Jio Institute Digital Library Search Results

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1. Editorial: New insights into caring for pediatric patients with cystic fibrosis

Author: Stephanie Bui, Laurence Delhaes, Gael Dournes, Philippe Reix, and Michael John Fayon
Subjects: cystic fibrosis, standard of care, modulators, telehealth, artificial inteligence, nutritional status, Pediatrics, RJ1-570
Published: 2023
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2. Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis

Author: Jérémy Reverchon, Vianney Tuloup, Romain Garreau, Viviane Nave, Sabine Cohen, Philippe Reix, Stéphane Durupt, Raphaele Nove-Josserand, Isabelle Durieu, Quitterie Reynaud, Laurent Bourguignon, Sandrine Charles, and Sylvain Goutelle
Subjects: cystic fibrosis, therapeutic drug monitoring, tobramycin, pharmacokinetics, model-informed precision dosing, Pharmacy and materia medica, RS1-441
Abstract: Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF.
Published: 2022
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3. Viral respiratory tract infections in young children with cystic fibrosis: a prospective full-year seasonal study

Author: Mathilde Eymery, Florence Morfin, Anne Doleans-Jordheim, Marie Perceval, Camille Ohlmann, Catherine Mainguy, and Philippe Reix
Subjects: Children, Respiratory virus, Cystic fibrosis, Infectious and parasitic diseases, RC109-216
Abstract: Abstract Background Viral respiratory tract infections are common during early childhood. How they impact cystic fibrosis lung disease history in young children is poorly known. The principal aim of our study was to determinate respiratory tract infections frequency in this cystic fibrosis young population. Secondary outcomes were nature of viral agents recovered and impact of such infections. Methods We conducted a prospective cohort study of 25 children affected by cystic fibrosis and aged less than 2 years. Nasal samplings were taken systematically monthly or bimonthly with additional samples taken during respiratory tract infections episodes. Ten pathogens were tested by a combination of five duplex RT-PCRs or PCRs: influenza A and B, respiratory syncytial virus (RSV), metapneumovirus (MPV), rhinovirus/enterovirus (RV/EV)), coronavirus (HKU1, NL63, 229E and OC43), parainfluenza virus (1–4), adenovirus and bocavirus (Respiratory Multi-Well System MWS r-gene®, BioMérieux, Marcy l’Étoile, France). Cycle thresholds (CTs) were reported for all positive samples and considered positive for values below 40. Quantitative variables were compared using a nonparametric statistical test (Wilcoxon signed rank for paired comparisons). Pearson’s correlation coefficient (r) was used to assess relationships between two variables. Statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, NC, USA) or GraphPad Prism V6.00 (GraphPad Software, La Jolla, CA, USA). The significance level was set at 0.05. Results The mean age at inclusion was 9.6 ± 6.7 months. The patients had 3.4 ± 1.7 respiratory tract infections episodes per child per year. Forty-four respiratory tract infections (69%) were associated with virus: rhinovirus and enterovirus (RV/EV) were implied in 61% of them and respiratory syncytial virus (RSV) in 14%. Only one patient required hospitalization for lower respiratory tract infections. 86% of the patients were treated by antibiotics for a mean of 13.8 ± 6.2 days. RSV infections (n = 6) were usually of mild severity. Conclusions Respiratory tract infections in young children with cystic fibrosis were of mild severity, rarely requiring hospitalization. Unsurprisingly, RV/EV were the most frequent agents. RSV-related morbidity seems low in this population. This raises the question of the usefulness of RSV preventive medication in this young population.
Published: 2019
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4. Impact of Coexistence Phenotype Between Staphylococcus aureus and Pseudomonas aeruginosa Isolates on Clinical Outcomes Among Cystic Fibrosis Patients

Author: Paul Briaud, Sylvère Bastien, Laura Camus, Marie Boyadjian, Philippe Reix, Catherine Mainguy, François Vandenesch, Anne Doléans-Jordheim, and Karen Moreau
Subjects: cystic fibrosis, infection, Staphylococcus aureus, Pseudomonas aeruginosa, clinical outcome, Microbiology, QR1-502
Abstract: Staphylococcus aureus (SA) is the major colonizer of the lungs of cystic fibrosis (CF) patients during childhood and adolescence. As patients age, the prevalence of SA decreases and Pseudomonas aeruginosa (PA) becomes the major pathogen infecting adult lungs. Nonetheless, SA remains significant and patients harboring both SA and PA are frequently found in the worldwide cohort. The overall impact of co-infection remains controversial. Furthermore, co-infecting isolates may compete or coexist. The aim of this study was to analyse if co-infection and the coexistence of SA and PA could lead to worse clinical outcomes. The clinical and bacteriological data of 212 Lyon CF patients were collected retrospectively, and patients were ranked into three groups, SA only (n = 112), PA only (n = 48) or SA plus PA (n = 52). In addition, SA and PA isolates from co-infected patients were tested in vitro to define their interaction profile. Sixty five percent (n = 34) of SA/PA pairs coexist. Using univariate and multivariate analysis, we confirm that SA patients have a less severe clinical condition than others, and PA induces a poor outcome independently of the presence of SA. Regarding co-infection, no significant difference in clinical outcomes was observed between patients with coexisting pairs and patients with competitive pairs. However, when compared to SA mono-infected patients, patients with coexisting pair presented higher frequency and length of hospitalizations and more exacerbations. We suggest that coexistence between SA and PA may be an important step in the natural history of lung bacterial colonization within CF patients.
Published: 2020
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5. Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles

Author: Ikrame Chouchane, Nathalie Stremler‐Lebel, and Philippe Reix
Subjects: azoles, cystic fibrosis, ivacaftor, lumacaftor, tacrolimus, Medicine, Medicine (General), R5-920
Abstract: Key Clinical Message We report the initiation of CFTR modulator lumacaftor/ivacaftor combination (LUM/IVA) in two adolescents with cystic fibrosis who were treated with antifungal azoles (AZO) and tacrolimus (TCS) for liver transplantation. Despite multiple drug‐drug interactions, maintaining therapeutic TCS levels was achievable. During the following year, LUM/IVA was well tolerated, providing clinical benefits.
Published: 2019
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6. Moving the Dial on Airway Inflammation in Response to Trikafta in Adolescents with Cystic Fibrosis

Author: Agathe, Lepissier, Anne Sophie, Bonnel, Nathalie, Wizla, Laurence, Weiss, Marie, Mittaine, Katia, Bessaci, Eitan, Kerem, Véronique, Houdouin, Philippe, Reix, Christophe, Marguet, Isabelle, Sermet-Gaudelus, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Référence Maladies Rares, Mucoviscidose et maladies apparentées (CRMR2MA / CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital de Hautepierre [Strasbourg], Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de pédiatrie générale et spécialisée [CHU de Reims - American Memorial Hospital] (SPGS), Centre Hospitalier Universitaire de Reims (CHU Reims)-American Memorial Hospital (Reims), Hadassah Hebrew University Medical Center [Jerusalem], Centre de ressources et de compétences pour la mucoviscidose [Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Cité (UPCité), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche sur le Handicap Ventilatoire (GRHV), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique Microbienne associée aux Infections Urinaires et Respiratoires (DYNAMICURE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Goethe-University Frankfurt am Main, and dormoy, valerian
Subjects: [SDV] Life Sciences [q-bio], Pulmonary and Respiratory Medicine, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Biomarker, Inflammation, Critical Care and Intensive Care Medicine, CFTR modulator
Abstract: International audience; No abstract available
Published: 2023

7. Profiling the response to lumacaftor-ivacaftor in children with cystic between fibrosis and new insight from a French-Italian real-life cohort

Author: Matthieu Cornet, Geneviève Robin, Fabiana Ciciriello, Tiphaine Bihouee, Christophe Marguet, Valérie Roy, Muriel Lebourgeois, Frédérique Chedevergne, Anne Sophie Bonnel, Mairead Kelly, Philippe Reix, Vincenzina Lucidi, Véronique Stoven, and Isabelle Sermet‐Gaudelus
Subjects: Pulmonary and Respiratory Medicine, Adolescent, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Aminopyridines, Aminophenols, Fibrosis, Anti-Bacterial Agents, Drug Combinations, Forced Expiratory Volume, Pediatrics, Perinatology and Child Health, Mutation, Humans, Benzodioxoles, Child
Abstract: Clinical trials for CFTR modulators consider mean changes of clinical status at the cohort level, and thus fail to assess the heterogeneity of the response. We aimed to study the different response profiles to lumacaftor-ivacaftor according to age in children with cystic fibrosis (CF).A mathematical framework, including principal component analysis, data clustering, and data completion, was applied to a multicenter cohort of 112 children aged 6-18 years, treated with lumacaftor-ivacaftor. Studied parameters at baseline and 6 months included body mass index (BMI), number of days of antibiotics (ATB), Sweat test (ST), forced expiratory volume in 1 s expressed in percentage predicted (ppFEVChange in ppFEVChange in ppFEV
Published: 2022

8. Human Papilloma Virus Vaccination Among Female Patients Attending French Pediatric Cystic Fibrosis Centers

Author: Christine Rousset-Jablonski, Philippe Reix, Isabelle Durieu, M. Perceval, C. Llerena, Angélique Denis, Julie Haesebaert, and S. Touzet
Subjects: Health Knowledge, Attitudes, Practice, Pediatrics, medicine.medical_specialty, Vaccination Coverage, Adolescent, Cystic Fibrosis, Vaccination schedule, Uterine Cervical Neoplasms, Disease, 03 medical and health sciences, 0302 clinical medicine, Health care, medicine, Humans, Papillomavirus Vaccines, 030212 general & internal medicine, Parent-Child Relations, Child, Reproductive health, 030219 obstetrics & reproductive medicine, Cervical screening, business.industry, Papillomavirus Infections, Obstetrics and Gynecology, Professional-Patient Relations, General Medicine, Odds ratio, Hepatitis B, medicine.disease, Vaccination, Cross-Sectional Studies, Pediatrics, Perinatology and Child Health, Female, France, Self Report, business
Abstract: Study Objective To describe human papilloma virus (HPV) vaccination practice among adolescent girls with cystic fibrosis (CF) and to identify reasons for non-vaccination. Design Cross-sectional multicentric study. Setting and Participants Girls aged 9-17 years, attending 7 French pediatric CF centers, and their accompanying adult. Interventions Administration of a self-report questionnaire. Main Outcome Measures The proportion of girls having received or receiving HPV vaccination, compliance with the vaccination schedule, factors associated with vaccination, and reasons for vaccination and for non-vaccination. Results A total of 113 girls and 104 accompanying adults participated. The mean age was 13.6 years (standard deviation 2.5; range 9-17). A total of 34 (30.9%) patients reported having received HPV vaccination. Among the 34 girls aged 15 years or older, 15 (44.1%) were vaccinated. Most patients (58.8%) started vaccination between 11 and 14 years of age (mean age 13.9). Most vaccine prescriptions (67.6%) were made by a CF center health care provider. Factors associated with vaccination were older age (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.01-1.6, P = .037 for each year older), previous vaccination by the accompanying parent of one of their children for hepatitis B (OR = 8.01, 95% CI = 0.96-67.02), P = .055), and parental influence on decision-making (OR = 2.77, 95% CI = 0.97-7.95, P = .058). Health care providers’ positive advice and fear of HPV-related disease were the main reasons given to justify vaccination decisions. Insufficient knowledge and concerns about potential side effects were the main barriers. Conclusion HPV vaccination remains insufficient among girls with CF. CF health care providers may play a crucial role in HPV vaccination acceptance, and their sensitization to cervical cancer prevention is mandatory.
Published: 2021

9. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for

Author: Marcus A, Mall, Rossa, Brugha, Silvia, Gartner, Julian, Legg, Alexander, Moeller, Pedro, Mondejar-Lopez, Dario, Prais, Tacjana, Pressler, Felix, Ratjen, Philippe, Reix, Paul D, Robinson, Hiran, Selvadurai, Florian, Stehling, Neil, Ahluwalia, Emilio, Arteaga-Solis, Bote G, Bruinsma, Mark, Jennings, Samuel M, Moskowitz, Sabrina, Noel, Simon, Tian, Tanya G, Weinstock, Pan, Wu, Claire E, Wainwright, and Jane C, Davies
Subjects: Cystic Fibrosis, Forced Expiratory Volume, Mutation, Humans, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, Child, Aminophenols, Chloride Channel Agonists
Published: 2022

10. A formalized transition program for cystic fibrosis: A 10‐year retrospective analysis of 97 patients in Lyon

Author: Isabelle Durieu, Fanny Magne, Raphaele Nove Josserand, Quitterie Reynaud, Philippe Reix, Gaelle Bourgeois, and Stéphane Durupt
Subjects: Adult, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Cystic Fibrosis, business.industry, Nutritional status, medicine.disease, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Outpatient visits, 030228 respiratory system, Forced Expiratory Volume, 030225 pediatrics, Pediatrics, Perinatology and Child Health, Retrospective analysis, Humans, Medicine, Child, business, Lung, Body mass index, Lung Transplantation, Retrospective Studies
Abstract: INTRODUCTION The prognosis of people diagnosed with cystic fibrosis (CF) has dramatically improved over the past decade in France, largely due to advances in CF care management, including an emphasis on chronic maintenance medications. Currently, the majority of French CF patients are adults, which means that they went through a transition process from receiving care at a pediatric CF center to receiving care at an adult CF center. To determine the impact of the transfer on clinical evolution, we report the transition procedure of our CF center in Lyon. MATERIALS AND METHODS From January 2006 to December 2016, 97 CF patients underwent a standardized process of transitioning from the pediatric to the adult CF center in Lyon. We compared the clinical evolution of these patients during three periods, starting the year before transition and ending the year after transition. Clinical data taken into account were forced expiratory volume in 1 s (FEV1 in liters), body mass index (BMI in kg/m2 ), pulmonary colonization, number of antibiotic courses, number of days of hospitalization per year, and outpatient visits per year. RESULTS No significant differences were observed between respiratory and nutritional status, respiratory microbiome, number of antibiotic courses, or number of hospitalizations or visits when comparing the threeperiods of observation around transition (the year before, the first year after, and the second year after transfer). CONCLUSION The standardized transition procedure used in Lyon is associated with the clinical stability of our CF patients.
Published: 2021

11. Risk factors for nontuberculous mycobacterial isolation in patients with cystic fibrosis: A meta‐analysis

Author: Raphaele Nove-Josserand, Stéphane Durupt, Pierre-Régis Burgel, Zoe Cavalli, Philippe Reix, Isabelle Durieu, Quitterie Reynaud, and Romain Bricca
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Cystic Fibrosis, Mycobacterium Infections, Nontuberculous, medicine.disease_cause, Azithromycin, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, 030225 pediatrics, Internal medicine, Humans, Medicine, biology, business.industry, Nontuberculous Mycobacteria, Odds ratio, bacterial infections and mycoses, biology.organism_classification, medicine.disease, Confidence interval, Stenotrophomonas maltophilia, 030228 respiratory system, Staphylococcus aureus, Meta-analysis, Pediatrics, Perinatology and Child Health, Nontuberculous mycobacteria, business, medicine.drug
Abstract: BACKGROUND To better understand the mechanisms of infection with nontuberculous mycobacteria (NTM) in patients with cystic fibrosis (CF), we explore different risk factors associated with NTM positivity in a meta-analysis. METHODS Studies published before 31 July 2019 were selected from MEDLINE. Combined odds ratios (ORs) were calculated by pooling the ORs of each study. The weighted mean difference (WMD) was used for continuous numerical measurements. Summary data were pooled using fixed- or random-effects models according to the presence of heterogeneity (P 50%). RESULTS Nineteen studies with a total of 23 418 patients, of whom 1421 (6%) were diagnosed as NTM positive, were included. Older age was significantly associated with NTM positivity (WMD = 2.12, 95% confidence interval [CI]: 1.11-3.13; P
Published: 2020

12. Population Pharmacokinetic Modeling and Dosing Simulations of Tobramycin in Pediatric Patients with Cystic Fibrosis

Author: Philippe Reix, Antonin Praet, Sylvain Goutelle, Florence Vetele, Laurent Bourguignon, Valentine Bréant, Oana Dumitrescu, Charlotte Genestet, and Anne Doleans-Jordheim
Subjects: medicine.medical_specialty, Cystic Fibrosis, Population, 030232 urology & nephrology, Urology, Cmax, 030226 pharmacology & pharmacy, 03 medical and health sciences, Cmin, 0302 clinical medicine, Pharmacokinetics, medicine, Tobramycin, Humans, Pharmacology (medical), Dosing, education, Child, Retrospective Studies, Pharmacology, education.field_of_study, medicine.diagnostic_test, business.industry, Bayes Theorem, Anti-Bacterial Agents, Infectious Diseases, Therapeutic drug monitoring, Pharmacodynamics, business, medicine.drug
Abstract: Initial dosing and dose adjustment of intravenous tobramycin in children with cystic fibrosis (CF) is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our children’s CF center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the ratios of maximal concentration to the MIC (C(max)/MIC) and daily area under the concentration-time curve to the MIC (AUC(24)/MIC) were considered efficacy targets. Trough concentration (C(min)) was considered the safety target. A total of 2,884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area, and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation in the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/pharmacodynamics (PD) simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve C(max)/MICs of ≥10 for MICs up to 2 mg/liter in most patients. The AUC(24)/MIC target was associated with higher dosage requirements and higher C(min). A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend performing tobramycin therapeutic drug monitoring (TDM), model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.
Published: 2021

13. Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Author: Patrick A Flume, Reta Fischer Biner, Damian G Downey, Cynthia Brown, Manu Jain, Rainald Fischer, Kris De Boeck, Gregory S Sawicki, Philip Chang, Hildegarde Paz-Diaz, Jaime L Rubin, Yoojung Yang, Xingdi Hu, David J Pasta, Stefanie J Millar, Daniel Campbell, Xin Wang, Neil Ahluwalia, Caroline A Owen, Claire E Wainwright, Ronald L. Gibson, Steven M. Rowe, Noah Lechtzin, Richard C. Ahrens, Karen S. McCoy, Moira Aitken, Scott H. Donaldson, Kimberly Ann McBennett, Joseph M. Pilewski, Joanne Billings, Carlos Milla, Ronald Rubenstein, Daniel Brian Rosenbluth, Rachel Linnemann, Michael R. Powers, Christopher Fortner, Carla Anne Frederick, Theodore G. Liou, Philip Black, Janice Wang, John L. Colombo, Maria Berdella, Maria Veronica Indihar, Cynthia D. Brown, Michael Anstead, Lara Bilodeau, Leonard Sicilian, James Jerome Tolle, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, Tara Lynn Barto, Nicholas Antos, John S. Rogers, Bryon Quick, Henry R. Thompson, Gregory Sawicki, Bruce Barnett, Robert L. Zanni, Thomas C. Smith, Karen D. Schultz, Claire Keating, Patrick Flume, Gregory J. Omlor, Alix Ashare, Karen Voter, Nighat Mehdi, Maria Gabriela Tupayachi Ortiz, Tonia E. Gardner, Steven R. Boas, Barbara Messore, Edith Zemanick, Raksha Jain, Michael McCarthy, Dana G. Kissner, Kapilkumar Patel, John McNamara, Julie Philley, Ariel Berlinski, Francisco J. Calimano, Terry Chin, Douglas Conrad, Cori Daines, Hengameh H. Raissy, Thomas G. Keens, Jorge E. Lascano, Bennie McWilliams, Brian Morrissey, Santiago Reyes, Subramanyam Chittivelu, Sabiha Hussain, Arvey Stone, James Wallace, Ross Klingsberg, Julie A. Biller, Stephanie Bui, Olaf Sommerburg, Elisabetta Bignamini, Mirella Collura, Alexander Moller, Donatello Salvatore, Chantal Belleguic, Lea Bentur, Ori Efrati, Eitan Kerem, Dario Prais, Esther Quintana Gallego, Peter Barry, Galit Livnat-Levanon, Jose Ramon Villa Asensi, David Stuart Armstrong, Oscar Asensio de la Cruz, Francis Gilchrist, Diana Elizabeth Tullis, Bradley Quon, Larry C. Lands, Nancy Morrison, Annick Lavoie, Barry Linnane, Okan Elidemir, Felix Ringshausen, Matthias Kappler, Helge Hebestreit, Jochen Mainz, Alexander Kiefer, Cordula Koerner-Rettberg, Doris Staab, Wolfgang Gleiber, Tacjana Pressler, Florian Stehling, Andreas Hector, Sivagurunathan Sutharsan, Lutz Naehrlich, Damian Downey, Jane Carolyn Davies, Robert Ian Ketchell, Mary Patricia Carroll, Simon Doe, Gordon MacGregor, Edward Fairbairn Nash, Nicholas Withers, Daniel Gavin Peckham, Martin James Ledson, Sonal Kansra, Timothy William Rayner Lee, Bertrand Delaisi, Gilles Rault, Jean Le Bihan, Dominique Hubert, Isabelle Fajac, Isabelle Sermet-Gaudelus, Marleen Bakker, Bert Arets, Christiane De Boeck, Raphael Chiron, Philippe Reix, Catherine Mainguy, Eva van Braeckel, Anne Malfroot, Isabelle Durieu, Nadine Desmazes Dufeu, Anne Prevotat, Renske van der Meer, Petrus Merkus, E.J.M. Weersink, Isabel Barrio Gomez-Aguero, Silvia Gartner, Amparo Sole Jover, Antonio Alvarez Fernandez, Desmond William Cox, Edward F. McKone, Barry James Plant, Hiranjan Selvadurai, Simon David Bowler, Claire Elizabeth Wainwright, Daniel Smith, Peter Gordon Middleton, John William Wilson, Sonia Volpi, Carla Colombo, Benedetta Fabrizzi, Vincenzina Lucidi, Federico Cresta, Salvatore Cucchiara, Ernst Eber, Helmut Ellemunter, Isidor Huttegger, Lena Hjelte, Christina Krantz, Marita Gilljam, and Pulmonology
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Indoles, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, Cystic fibrosis, Time, Ivacaftor, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Clinical endpoint, Humans, Benzodioxoles, 030212 general & internal medicine, Israel, biology, business.industry, Australia, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Discontinuation, Europe, Drug Combinations, Treatment Outcome, Clinical research, 030228 respiratory system, Tolerability, Mutation, North America, biology.protein, Female, business, medicine.drug
Abstract: Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.
Published: 2021

14. Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis

Author: Laurent Mely, E. Battistella, Martine Reynaud-Gaubert, Trieu-Nghi Hoang-Thi, Guillaume Chassagnon, Christophe Marguet, Annlyse Fanton, Marie-Pierre Revel, Raphaël Chiron, Chantal Belleguic, Maria Vakalopoulou, Clémence Martin, Stéphanie Bui, Pierre-Régis Burgel, Marlène Murris-Espin, Alienor Campredon, Jennifer Da Silva, Isabelle Durieu, Philippe Reix, OPtimisation Imagerie et Santé (OPIS), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-CentraleSupélec-Université Paris-Saclay, Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), and CentraleSupélec-Université Paris-Saclay
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung, biology, business.industry, Lumacaftor, Chest ct, medicine.disease, Cystic fibrosis, Cystic fibrosis transmembrane conductance regulator, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Ivacaftor, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Lung disease, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, biology.protein, Radiology, business, Lung function, medicine.drug
Abstract: ObjectivesLumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor.MethodsAdolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans.ResultsA total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (−1.40±1.53 points compared with pretherapeutic CT; p1) ≥5 under lumacaftor–ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01).ConclusionOne year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.
Published: 2021

15. Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis

Author: Aurélie Tatopoulos, Philippe Reix, Marie Luce Choukroun, Pierre-Régis Burgel, Katia Bessaci-Kabouya, Iulia Ioan, Jennifer Da Silva, Muriel Le Bourgeois, Plamen Bokov, M. Gerardin, Jean-Louis Paillasseur, Stéphanie Bui, Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), and Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Adolescent, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Aminopyridines, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, Cystic fibrosis, Ivacaftor, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Daily practice, Medicine, Humans, Benzodioxoles, Young adult, 10. No inequality, Chloride Channel Agonists, ComputingMilieux_MISCELLANEOUS, business.industry, Lumacaftor, medicine.disease, 3. Good health, Respiratory Function Tests, Drug Combinations, 030104 developmental biology, 030228 respiratory system, chemistry, Lung disease, Pediatrics, Perinatology and Child Health, Biomarker (medicine), Observational study, business, medicine.drug
Abstract: Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.
Published: 2021

16. Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis

Author: Nathalie Wizla-Derambure, Marie Mittaine, E. Deneuville, Michael Fayon, Christophe Marguet, Ludovic Lemée, Véronique Houdouin, Michel Abely, Philippe Reix, S. Ramel, Laure Couderc, Marie-Laure Dalphin, Muriel Le Bourgeois, Evelyne Leroux, Isabelle Pin, F. Huet, Harriet Corvol, Tiphaine Bihouée, Muriel Laurans, Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU de Bordeaux Pellegrin [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pneumologie et d'Allergologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Mucoviscidose: physiopathologie et phénogénomique [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Vaincre la Mucoviscidose, Association de lutte contre la Mucoviscidose, Normandie Université (NU)-Normandie Université (NU), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-SU, Gestionnaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Service de Pneumologie pédiatrique [CHU Trousseau]
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, lcsh:Medicine, Chest physiotherapy, medicine.disease_cause, Cystic fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Haemophilus influenzae, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, medicine, 030212 general & internal medicine, Respiratory infections and tuberculosis, CF and non-CF bronchiectasis, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Lung, Paediatric pulmonology, Pseudomonas aeruginosa, business.industry, lcsh:R, medicine.disease, 3. Good health, medicine.anatomical_structure, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Staphylococcus aureus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Sputum, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business, Airway
Abstract: Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients.This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection.300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection.The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.
Published: 2021

17. HOMA indices as screening tests for cystic fibrosis-related diabetes

Author: Catherine Mainguy, Isabelle Durieu, S. Touzet, Quitterie Reynaud, Angélique Denis, Philippe Reix, Catherine Llerena, Tom Toin, and Isabelle Pin
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Adult, Blood Glucose, Male, medicine.medical_specialty, endocrine system diseases, Screening test, Adolescent, Cystic Fibrosis, Cystic fibrosis-related diabetes, Cystic fibrosis, Gastroenterology, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Insulin resistance, Age groups, Predictive Value of Tests, Positive predicative value, Diabetes mellitus, Internal medicine, Insulin-Secreting Cells, medicine, Diabetes Mellitus, Humans, Insulin, Prospective Studies, Prospective cohort study, Child, business.industry, nutritional and metabolic diseases, Glucose Tolerance Test, medicine.disease, 030104 developmental biology, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Female, Insulin Resistance, business, hormones, hormone substitutes, and hormone antagonists, Biomarkers
Abstract: We assessed the diagnostic performances of homeostasis model assessment indices (HOMA) of β-cell function (HOMA-%β) and of insulin resistance (HOMA-IR) for cystic fibrosis related diabetes (CFRD) screening.Data were collected from a prospective cohort of 228 patients with CF (117 adults and 111 children). Fasting insulin and glucose levels were measured to calculate HOMA-%β and HOMA-IR. HOMA-%β100 indicated insulin secretion deficiency and HOMA-IR1 insulin resistance. Both were used to calculate sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Two-hour oral glucose tolerance tests (2h-OGTT) defined CFRD. Analyses were conducted separately for children and adults. Performances of HOMA-%β and HOMA-IR were calculated at inclusion, for each year of follow-up and for pooled data over the follow-up period.Sensitivity, specificity, NPV and PPV were respectively: 88%, 45%, 98% and 11% for HOMA-%β and 42%, 48%, 91% and 6% for HOMA-IR in the pooled data of children; and 83%, 18%, 90% and 10% for HOMA-%β, and 39%, 80%, 92% and 18% for HOMA-IR in the pooled data of adults. Combining HOMA-%β and HOMA-IR did not improve performances.Within both age groups, HOMA-%β100 provided good sensitivity and NPV. HOMA-IR1 had low sensitivity. Calculation of the HOMA-%β could be an interesting first-line screening approach to exclude CFRD and thus avoid unnecessary OGTT in patients for whom value is ≥100. However, HOMA-%β100 does not support the diagnosis of CFRD and should be complemented by OGTT.
Published: 2021

18. Chest physiotherapy enhances detection of

Author: Christophe, Marguet, Véronique, Houdouin, Isabelle, Pin, Philippe, Reix, Frédéric, Huet, Marie, Mittaine, Sophie, Ramel, Nathalie, Wizla-Derambure, Michel, Abely, Marie-Laure, Dalphin, Michael, Fayon, Tiphaine, Bihouée, Muriel, Le Bourgeois, Eric, Deneuville, Harriet, Corvol, Muriel, Laurans, Laure, Couderc, Evelyne, Leroux, and Ludovic, Lémée
Subjects: Cystic Fibrosis, Original Articles
Abstract: Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF., Sputum collection after a chest physiotherapy session strongly enhances the detection of P. aeruginosa in nonexpectorating CF children compared with the commonly used oropharyngeal swab method. Oropharyngeal swab after physiotherapy may be an acceptable alternative. https://bit.ly/3757ewq
Published: 2020

19. Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function

Author: Marlène Murris-Espin, Christophe Marguet, Anne Munck, Michel Abely, Harriet Corvol, Philippe Reix, Laurent Mely, Clémence Martin, Tiphaine Biouhee, Julie Macey, Michele Porzio, A. Prevotat, Stéphanie Bui, Dominique Hubert, Isabelle Sermet-Gaudelus, Jennifer Da Silva, Clémence Dehillotte, Isabelle Durieu, Lydie Lemonnier, Raphaël Chiron, Pierre-Régis Burgel, Jean-Louis Paillasseur, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Hôpital Renée Sabran [CHU - HCL], Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), CHU Strasbourg, American Memorial Hospital (Hôpital des enfants) [Reims], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes (GRAM 1.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Mucoviscidose: physiopathologie et phénogénomique [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Robert Debré, Vaincre la Mucoviscidose, Association de lutte contre la Mucoviscidose, EFFI-STAT, and Centre Hospitalier Universitaire de Reims (CHU Reims)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Adolescent, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Aminopyridines, Quinolones, Aminophenols, Cystic fibrosis, Ivacaftor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, In patient, Benzodioxoles, Chloride Channel Agonists, Lung function, ComputingMilieux_MISCELLANEOUS, business.industry, Lumacaftor, Authorization, medicine.disease, 3. Good health, Respiratory Function Tests, Drug Combinations, 030104 developmental biology, Cftr mutation, 030228 respiratory system, chemistry, Pediatrics, Perinatology and Child Health, Disease Progression, Female, France, business, medicine.drug
Abstract: International audience; Background: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1.Methods: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1
Published: 2020

20. Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis

Author: Laurianne Coutier, Camille Ohlmann, Catherine Mainguy, M. Perceval, Aurélie Labaste, Philippe Reix, and V. Jubin
Subjects: Male, Pulmonary and Respiratory Medicine, Adolescent, Cystic Fibrosis, Aminopyridines, Quinolones, Aminophenols, Cystic fibrosis, Ivacaftor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Forced Expiratory Volume, medicine, Humans, Benzodioxoles, 030212 general & internal medicine, Respiratory system, Chloride Channel Agonists, Inhalation, business.industry, Lumacaftor, respiratory system, Airway obstruction, medicine.disease, Respiratory Function Tests, respiratory tract diseases, Drug Combinations, Treatment Outcome, 030228 respiratory system, chemistry, Anesthesia, Pediatrics, Perinatology and Child Health, Salbutamol, Female, Bronchoconstriction, France, Drug Monitoring, Symptom Assessment, medicine.symptom, business, circulatory and respiratory physiology, medicine.drug
Abstract: The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV1 were more at risk of FEV1 decrease.
Published: 2017

21. Palivizumab prophylaxis in infants with cystic fibrosis does not delay first isolation of Pseudomonas aeruginosa or Staphylococcus aureus

Author: Stéphane Sanchez, Behrouz Kassai-Koupai, Marie-Laure Dalphin, Philippe Reix, Laurianne Coutier, Clélia Buchs, Catherine Mainguy, and M. Perceval
Subjects: Male, Palivizumab, Staphylococcus aureus, medicine.medical_specialty, Pediatrics, Cystic Fibrosis, Respiratory Syncytial Virus Infections, medicine.disease_cause, Staphylococcal infections, Antiviral Agents, Injections, Intramuscular, Cystic fibrosis, Drug Administration Schedule, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, medicine, Humans, Pseudomonas Infections, Respiratory system, Retrospective Studies, Pseudomonas aeruginosa, business.industry, Age Factors, Case-control study, Infant, Retrospective cohort study, Staphylococcal Infections, medicine.disease, Treatment Outcome, 030228 respiratory system, Case-Control Studies, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business, Follow-Up Studies, medicine.drug
Abstract: Respiratory syncytial virus (RSV) infections may worsen cystic fibrosis (CF) lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients. We aimed to determine the effectiveness of PVZ on microbiological outcomes in young children with CF. We conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140). One case was matched with at least three same-gender controls born the same year and month. Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8-32.6] months) and PVZ+ (10.4 [1.2-33.0] months; p = 0.953) patients. A similar trend was found for Sa (PVZ+: 6.4 [2.0-59.0] months; PVZ-: 3.8 [0.1-74.1] months; p = 0.191). The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40% vs. PVZ- 41.4%), but this proportion was higher for Sa in the PVZ+ group (97%) than in the PVZ- group (85%; p = 0.001). Healthcare consumption and growth outcomes did not significantly differ between groups.Systematic PVZ use did not delay key pathogen acquisition in young children with CF. What is known: • Palivizumab is the only available monoclonal antibody against respiratory syncytial virus infection. • Whether or not it is useful in infants with cystic fibrosis remains controversial. What is new: • Palivizumab does not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with cystic fibrosis. • Palivizumab does not reduce healthcare consumption or improve growth during the first 3 years of life of young children with cystic fibrosis.
Published: 2017

22. WS15.3 HOMA indexes diagnosis performance for Cystic Fibrosis-Related Diabetes

Author: Catherine Mainguy, S. Touzet, T. Toin, Isabelle Durieu, Quitterie Reynaud, Philippe Reix, and Angélique Denis
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Internal medicine, Pediatrics, Perinatology and Child Health, Cystic fibrosis-related diabetes, medicine, medicine.disease, business, Cystic fibrosis, Gastroenterology
Published: 2020

23. Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis

Author: Pierre-Régis Burgel, Anne Munck, Isabelle Durieu, Raphaël Chiron, Laurent Mely, Anne Prevotat, Marlene Murris-Espin, Michele Porzio, Michel Abely, Philippe Reix, Christophe Marguet, Julie Macey, Isabelle Sermet-Gaudelus, Harriet Corvol, Stéphanie Bui, Lydie Lemonnier, Clémence Dehillotte, Jennifer Da Silva, Jean-Louis Paillasseur, Dominique Hubert, Julie Mounard, Claire Poulet, Cinthia Rames, Christine Person, Françoise Troussier, Thierry Urban, Marie-Laure Dalphin, Jean-Claude Dalphin, Didier Pernet, Bénédicte Richaud-Thiriez, Mickael Fayon, Julie Macey-Caro, Karine Campbell, Muriel Laurans, Corinne Borderon, Marie-Christine Heraud, André Labbé, Sylvie Montcouquiol, Laurence Bassinet, Natascha Remus, Annlyse Fanton, Anne Houzel-Charavel, Frédéric Huet, Stéphanie Perez-Martin, Amale Boldron-Ghaddar, Manuela Scalbert, Boubou Camara, Catherine Llerena, Isabelle Pin, Sébastien Quétant, Aurélie Cottereau, Antoine Deschildre, Alice Gicquello, Thierry Perez, Lidwine Stervinou-Wemeau, Caroline Thumerelle, Benoit Wallaert, Nathalie Wizla, Jane Languepin, Céline Ménétrey, Magalie Dupuy-Grasset, Lucie Bazus, Clelia Buchs, Virginie Jubin, Marie-Christine Werck-Gallois, Catherine Mainguy, Thomas Perrin, Agnès Toutain-Rigolet, Stéphane Durupt, Quitterie Reynaud, Raphaele Nove-Josserand, Melisande Baravalle-Einaudi, Bérangère Coltey, Nadine Dufeu, Jean-Christophe Dubus, Nathalie Stremler, Davide Caimmi, Yves Billon, Jocelyne Derelle, Sébastien Kieffer, Anne-Sophie Pichon, Cyril Schweitzer, Aurélie Tatopoulos, Sarah Abbes, Tiphaine Bihouée, Isabelle Danner-Boucher, Valérie David, Alain Haloun, Adrien Tissot, Sylvie Leroy, Carole Bailly-Piccini, Annick Clément, Aline Tamalet, Isabelle Honoré, Reem Kanaan, Clémence Martin, Cécile Bailly, Frédérique Chédevergne, Jacques De Blic, Brigitte Fauroux, Murielle Le Bourgeois, Bertrand Delaisi, Michèle Gérardin, Michel Abély, Bruno Ravoninjatovo, Chantal Belleguic, Benoit Desrues, Graziella Brinchault, Michel Dagorne, Eric Deneuville, Sylvaine Lefeuvre, Anne Dirou, Jean Le Bihan, Sophie Ramel, Stéphane Dominique, Annabelle Payet, Romain Kessler, Vincent Rosner, Laurence Weiss, Sandra de Miranda, Dominique Grenet, Abdoul Hamid, Clément Picard, François Brémont, Alain Didier, Géraldine Labouret, Marie Mittaine, Marlène Murris-Espin, Laurent Têtu, Laure Cosson, Charlotte Giraut, Anne-Cécile Henriet, Julie Mankikian, Sophie Marchand, Sandrine Hugé, Véronique Storni, Emmanuelle Coirier-Duet, CHU Cochin [AP-HP], Service de Médecine Interne - Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Association Vaincre La Mucoviscidose, Institut Cochin (IC UM3 (UMR 8104 / U1016)), EFFI-STAT, CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mucoviscidose: physiopathologie et phénogénomique [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Ressources et de Compétences en Mucoviscidose [CHU Toulouse] (CRCM Toulouse), Service Pneumologie et allergologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Cystic Fibrosis, Gastrointestinal Diseases, [SDV]Life Sciences [q-bio], Aminopyridines, Quinolones, Critical Care and Intensive Care Medicine, Logistic regression, Aminophenols, Cystic fibrosis, Body Mass Index, Ivacaftor, chemistry.chemical_compound, 0302 clinical medicine, Deprescriptions, Forced Expiratory Volume, Medicine, 030212 general & internal medicine, Fatigue, 2. Zero hunger, biology, Lumacaftor, Headache, lumacaftor–ivacaftor, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Anti-Bacterial Agents, Drug Combinations, Treatment Outcome, Administration, Intravenous, Female, France, medicine.drug, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Metrorrhagia, Adolescent, Nutritional Status, 03 medical and health sciences, Young Adult, Internal medicine, Product Surveillance, Postmarketing, Humans, Benzodioxoles, Adverse effect, Bronchial Spasm, business.industry, Editorials, Myalgia, medicine.disease, Discontinuation, Dyspnea, Logistic Models, 030228 respiratory system, chemistry, Cough, Multivariate Analysis, biology.protein, postmarketing study, business, Body mass index
Abstract: International audience; Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.
Published: 2019

24. Do patients with cystic fibrosis participating in clinical trials demonstrate placebo response ? A meta-analysis

Author: François Gueyffier, Behrouz Kassai-Koupai, Perrine Janiaud, Julie Coton, Michel Cucherat, Ha-Hai Le, and Philippe Reix
Subjects: Clinical trial, medicine.medical_specialty, Placebo response, business.industry, Internal medicine, Meta-analysis, Medicine, business, medicine.disease, Cystic fibrosis
Published: 2019

25. Viral respiratory tract infections in young children with cystic fibrosis: a prospective full-year seasonal study

Author: Camille Ohlmann, Catherine Mainguy, Mathilde Eymery, Anne Doléans-Jordheim, Philippe Reix, M. Perceval, Florence Morfin, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, viruses, [SDV]Life Sciences [q-bio], Population, Respiratory Syncytial Virus Infections, Respiratory virus, Biology, medicine.disease_cause, Severity of Illness Index, Cystic fibrosis, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Virology, medicine, Humans, lcsh:RC109-216, Prospective Studies, Respiratory system, education, Respiratory Tract Infections, Children, Coronavirus, education.field_of_study, Picornaviridae Infections, Respiratory tract infections, Coinfection, Research, Infant, medicine.disease, 3. Good health, 030104 developmental biology, Infectious Diseases, Viruses, Enterovirus, Female, 030211 gastroenterology & hepatology, France, Seasons, Rhinovirus, Coronavirus Infections
Abstract: Viral respiratory tract infections are common during early childhood. How they impact cystic fibrosis lung disease history in young children is poorly known. The principal aim of our study was to determinate respiratory tract infections frequency in this cystic fibrosis young population. Secondary outcomes were nature of viral agents recovered and impact of such infections. We conducted a prospective cohort study of 25 children affected by cystic fibrosis and aged less than 2 years. Nasal samplings were taken systematically monthly or bimonthly with additional samples taken during respiratory tract infections episodes. Ten pathogens were tested by a combination of five duplex RT-PCRs or PCRs: influenza A and B, respiratory syncytial virus (RSV), metapneumovirus (MPV), rhinovirus/enterovirus (RV/EV)), coronavirus (HKU1, NL63, 229E and OC43), parainfluenza virus (1–4), adenovirus and bocavirus (Respiratory Multi-Well System MWS r-gene®, BioMerieux, Marcy l’Etoile, France). Cycle thresholds (CTs) were reported for all positive samples and considered positive for values below 40. Quantitative variables were compared using a nonparametric statistical test (Wilcoxon signed rank for paired comparisons). Pearson’s correlation coefficient (r) was used to assess relationships between two variables. Statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, NC, USA) or GraphPad Prism V6.00 (GraphPad Software, La Jolla, CA, USA). The significance level was set at 0.05. The mean age at inclusion was 9.6 ± 6.7 months. The patients had 3.4 ± 1.7 respiratory tract infections episodes per child per year. Forty-four respiratory tract infections (69%) were associated with virus: rhinovirus and enterovirus (RV/EV) were implied in 61% of them and respiratory syncytial virus (RSV) in 14%. Only one patient required hospitalization for lower respiratory tract infections. 86% of the patients were treated by antibiotics for a mean of 13.8 ± 6.2 days. RSV infections (n = 6) were usually of mild severity. Respiratory tract infections in young children with cystic fibrosis were of mild severity, rarely requiring hospitalization. Unsurprisingly, RV/EV were the most frequent agents. RSV-related morbidity seems low in this population. This raises the question of the usefulness of RSV preventive medication in this young population.
Published: 2019
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26. Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis

Author: Diana Bilton, Tacjana Pressler, Isabelle Fajac, John Paul Clancy, Dorota Sands, Predrag Minic, Marco Cipolli, Ivanka Galeva, Amparo Solé, Alexandra L. Quittner, Keith Liu, John P. McGinnis, Gina Eagle, Renu Gupta, Michael W. Konstan, Sabine Renner, Christiane Knoop, Anne Malfroot, Lieven Dupont, Kristine Desager, Frans De Baets, Miroslava Bosheva, Vania Nedkova, Ivan Galabov, Andreas Freitag, Nancy Morrison, Pearce Wilcox, Tanja Pressler, Yves Martinet, Raphael Chiron, Stephan Dominique, Philippe Reix, Anne Prevotat, Isabelle Sermet, Isabelle Durieu, Rainald Fischer, Rudolf Huber, Doris Staab, Uwe Mellies, Wolfgang Sextro, Tobias Welte, Heinrike Wilkens, Urte Sommerwerk, Burkhard Bewig, Ilias Inglezos, Stavros-Eleftherios Doudounakis, Olga Bede, Ferenc Gönczi, Rita Újhelyi, Edward McKone, Paul McNally, Vincenzina Lucidi, Mario La Rosa, Laura Minicucci, Rita Padoan, Giovanna Pisi, Rolando Gagliardini, Carla Colombo, Inez Bronsveld, Ewa Sapiejka, Henryk Mazurek, Grażyna Górnicka, Iwona Stelmach, Halina Batura-Gabryel, Marta Rachel, Jaroslava Orosova, Branko Takac, Anna Feketova, Carmen Martinez, Gloria Garcia Hernandez, Jose Ramon Villa-Asensi, Silvia Gartner, Amparo Sole, Anders Lindblad, Martin Ledson, Joanna Whitehouse, Alan Smyth, Ian Ketchell, Timothy Lee, and Gordon MacGregor
Subjects: 0301 basic medicine, Male, Cystic Fibrosis, Gastroenterology, Cystic fibrosis, 0302 clinical medicine, Surveys and Questionnaires, Tobramycin, education.field_of_study, Inhalation, Symptom Flare Up, 3. Good health, Anti-Bacterial Agents, Respiratory Function Tests, Hospitalization, medicine.anatomical_structure, Treatment Outcome, Amikacin, Pseudomonas aeruginosa, Female, medicine.symptom, Symptom Assessment, medicine.drug, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Population, Article, 03 medical and health sciences, Internal medicine, Administration, Inhalation, medicine, Humans, Pseudomonas Infections, education, Adverse effect, Lung, Dose-Response Relationship, Drug, business.industry, Sputum, medicine.disease, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Liposomes, business
Abstract: Background Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. Methods Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. Conclusions Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678
Published: 2019

27. Do patients with cystic fibrosis participating in clinical trials demonstrate placebo response? A meta-analysis

Author: Perrine Janiaud, Philippe Reix, Julie Coton, Michel Cucherat, Ha-Hai Le, Behrouz Kassai-Koupai, Victor Veuillet, François Gueyffier, Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie Pédiatrique [Hôpital Femme Mère Enfant - CHU de Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-lyon
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Vital capacity, Cystic Fibrosis, Cystic fibrosis, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Internal medicine, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, Clinical Trials as Topic, Placebo response, business.industry, Placebo Effect, medicine.disease, Confidence interval, 3. Good health, Clinical trial, Treatment Outcome, 030104 developmental biology, 030228 respiratory system, Meta-analysis, Pediatrics, Perinatology and Child Health, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Body mass index
Abstract: Background Patients' and families' expectation that a cure for cystic fibrosis (CF) will be found is high. In other debilitating conditions, high expectation has been shown to drive a strong placebo response (PR). Therefore, our goal was to evaluate PR on objective continuous outcomes (FEV1, BMI) and the CF Questionnaire Revised-Respiratory Domain (CFQR-RD) monitored during randomised clinical trials (RCTs) for CF. Methods We conducted a meta-analysis after a systematic review of the literature carried out to identify RCTs with FEV1, CFQR-RD and BMI as outcome measures. The standardised mean difference (SMD) was calculated to estimate the PR. A meta-regression analysis was conducted to assess other contributing factors on PR such as study design, trial duration, patient age and disease severity. Results Out of 289 RCTs found in the search, we identified 61 articles (published from 1987 to 2017) with respectively 59, 17 and 9 reporting FEV1, CFQR-RD and BMI at the start and at the end of the RCTs. No significant PR was found on FEV1 or CFQR-RD. However, a small but significant PR was found on BMI SMD, 0.09 (95% CI (0.01; 0.17); p = 0.03). Conclusion The PR seems higher when measuring BMI. However, it is not clear whether this improvement can be explained by a PR alone.
Published: 2019

28. Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients

Author: Isabelle Durieu, Soazic Grard, Benyebka Mammar, Dominique Hubert, Raphaele Nove-Josserand, Philippe Reix, Lila Auzou, Laurent Mely, Marlène Murris-Espin, Pierre-Régis Burgel, and François Bremont
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, biology, business.industry, Context (language use), Omalizumab, Immunoglobulin E, medicine.disease, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, Concomitant, Pediatrics, Perinatology and Child Health, medicine, biology.protein, 030212 general & internal medicine, Allergic bronchopulmonary aspergillosis, Adverse effect, business, Body mass index, medicine.drug
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) affects up to 15% of patients with cystic fibrosis (CF). Corticosteroids are used as first-line therapy, but relapse and adverse effects commonly occur. Case reports have suggested the efficacy of the anti-IgE recombinant humanized monoclonal antibody omalizumab. A retrospective multicenter observational French study retrieved 32 CF patients (11 children and 21 adults) who have received omalizumab for more than 3 months in the context of ABPA. Clinical characteristics, concomitant medications (inhaled and oral corticosteroids, antifungal drugs), lung function, body mass index (BMI), and serum IgE were compared at the start and during the first year of omalizumab therapy. Omalizumab-related adverse effects and costs were also evaluated. No significant difference with omalizumab could be demonstrated with regard to lung function, BMI, or the number of patients receiving oral corticosteroids. At the time of initiation of omalizumab, 56% of patients were receiving oral corticosteroids. Five patients were able to discontinue corticosteroids during follow-up and nine patients were able to reduce their daily dose. A total of 78% of the patients had received antifungal therapy at the time of the initiation of omalizumab. Treatment tolerance was good (12.5% of patients experienced side effects). The median cost of omalizumab treatment was €3,620 per patient per month. Omalizumab may represent a steroid-sparing therapy in CF patients with ABPA. A randomized-controlled trial is urgently required to provide higher level of evidence regarding the efficacy and cost-effectiveness of omalizumab in CF patients with ABPA. Pediatr Pulmonol. 2017;52:190-197. © 2016 Wiley Periodicals, Inc.
Published: 2016

29. Maladie osseuse liée à la mucoviscidose : mise au point

Author: Philippe Reix, Justine Bacchetta, and C. Braun
Subjects: medicine.medical_specialty, Bone disease, Bone density, medicine.diagnostic_test, business.industry, Bone fracture, medicine.disease, Gastroenterology, Asymptomatic, Cystic fibrosis, Bone remodeling, 03 medical and health sciences, Bone Density Conservation Agents, 0302 clinical medicine, 030228 respiratory system, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, 030212 general & internal medicine, medicine.symptom, Quantitative computed tomography, business
Abstract: With the increasing life expectancy of patients with cystic fibrosis (CF), prevalence of late complications such as CF-related bone disease (CFBD) has increased. It was initially described in 24% of the adult population with CF and has also been reported in the pediatric population. CFBD is multifactorial and progresses in different steps. Both decreased bone formation and increased bone resorption (in different amounts) are observed. CFBD is likely primitive (directly related to the CFTR defect itself), but is also worsened by acquired secondary factors such as lung infections, chronic inflammation, denutrition, vitamin deficiency, and decreased physical activity. CFBD may be clinically apparent (i.e., mainly vertebral and costal fractures), or clinically asymptomatic (therefore corresponding to abnormalities in bone density and architecture). CFBD management mainly aims to prevent the occurrence of fractures. Prevention and regular monitoring of bone disease as early as 8 years of age is of the utmost importance, as is the control of possible secondary deleterious CFBD factors. New radiological tools, such as high-resolution peripheral quantitative computed tomography, allow an accurate evaluation of cortical and trabecular bone micro-architecture in addition to compartmental density; as such, they will likely improve the assessment of the bone fracture threat in CF patients in the near future.
Published: 2016

30. P153 Population PK analysis and dosing simulation of tobramycin in paediatric patients with cystic fibrosis

Author: S. Goutelle, Philippe Reix, A. Praet, Anne Doléans-Jordheim, L. Bourguignon, V. Bréant, Oana Dumitrescu, and F. Vételé
Subjects: Pulmonary and Respiratory Medicine, education.field_of_study, medicine.medical_specialty, business.industry, Population, medicine.disease, Cystic fibrosis, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Tobramycin, Dosing, education, business, Paediatric patients, medicine.drug
Published: 2020

31. WS01.1 Low frequency of confirmed hypersensitivity to antibiotics in cystic fibrosis patients

Author: V. Jubin, Isabelle Durieu, C. Braun, Camille Ohlmann, A. Nosbaum, Catherine Mainguy, Philippe Reix, Raphaele Nove-Josserand, Stéphane Durupt, and J.-F. Nicolas
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, medicine.drug_class, Internal medicine, Pediatrics, Perinatology and Child Health, Antibiotics, Medicine, business, medicine.disease, Gastroenterology, Cystic fibrosis
Published: 2020

32. P131 Most of Staphylococcus aureus and Pseudomonas aeruginosa coinfecting isolates coexist, a condition that may impact clinical outcomes in cystic fibrosis patients

Author: Philippe Reix, Anne Doléans-Jordheim, Karen Moreau, Paul Briaud, Laura Camus, S. Bastien, François Vandenesch, M. Boyadjian, and Catherine Mainguy
Subjects: Pulmonary and Respiratory Medicine, business.industry, Staphylococcus aureus, Pseudomonas aeruginosa, Pediatrics, Perinatology and Child Health, Medicine, business, medicine.disease_cause, medicine.disease, Cystic fibrosis, Microbiology
Published: 2020

33. Glucose trajectories in cystic fibrosis and their association with pulmonary function

Author: Sylvain Roche, Muriel Rabilloud, C. Llerena, Jean Iwaz, Philippe Reix, Raphaele Nove-Josserand, Isabelle Durieu, Emilie Blond, S. Poupon-Bourdy, Martine Laville, Quitterie Reynaud, Sébastien Quétant, Sandrine Touzet, Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de Biostatistiques [Lyon], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Pôle Information Médicale Evaluation Recherche (IMER), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire [Grenoble] (CHU), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Blood Glucose, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pediatrics, Cystic Fibrosis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cystic fibrosis-related diabetes, 030209 endocrinology & metabolism, Cystic fibrosis, Body Mass Index, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Glucose Intolerance, Diabetes Mellitus, medicine, Humans, Respiratory system, Child, Correlation of Data, ComputingMilieux_MISCELLANEOUS, business.industry, Insulin, Glucose Tolerance Test, medicine.disease, Respiratory Function Tests, 3. Good health, Endocrinology, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Disease Progression, Female, France, Abnormality, business, Body mass index
Abstract: Background The prevalence of cystic fibrosis-related diabetes is increasing. This condition is potentially responsible for respiratory decline. Methods At inclusion, then yearly (over three years), 111 children and 117 adults with cystic fibrosis had oral glucose tolerance and insulin tests at one (G1) and 2h (G2). KmL analysis identified homogeneous G1 and G2 glucose trajectories. A linear mixed model quantified the relationships between trajectories and FEV1 changes. Results In children, there were three G1 and four G2 trajectories and FEV1 decrease was not significantly different between G1 or G2 trajectories. In adults, two G1 and four G2 trajectories were identified and FEV1 change was estimated at −0.85/year (95% CI: [−1.54; −0.17], p=0.01) whatever the G1 trajectory and found significantly faster in the high and increasing G2 trajectory (−2.1/year, [−3.9; −0.2], p=0.03). Conclusions In case of persistent G2 abnormality, physicians should be alert for clinical deterioration and intensify patient surveillance.
Published: 2018

34. Nutritional Status in the First 2 Years of Life in Cystic Fibrosis Diagnosed by Newborn Screening

Author: Anne, Munck, Rym, Boulkedid, Laurence, Weiss, Pierre, Foucaud, Nathalie, Wizla-Derambure, Philippe, Reix, François, Bremont, Jocelyne, Derelle, Julien, Schroedt, Corinne, Alberti, and Laure, Couderc
Subjects: Male, Pediatrics, medicine.medical_specialty, Staphylococcus aureus, Cystic Fibrosis, Body height, Enzyme Therapy, Nutritional Status, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Neonatal Screening, 030225 pediatrics, Medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Prospective Studies, Prospective cohort study, Respiratory Tract Infections, Growth Disorders, Newborn screening, business.industry, Nutritional Support, Body Weight, Malnutrition, Gastroenterology, Infant, Newborn, Infant, Nutritional status, Avitaminosis, Proton Pump Inhibitors, Vitamins, medicine.disease, Body Height, Breast Feeding, Multicenter study, Child, Preschool, Pediatrics, Perinatology and Child Health, Cohort, Carrier State, Pseudomonas aeruginosa, Exocrine Pancreatic Insufficiency, Female, business, Breast feeding
Abstract: To evaluate nutritional status and associated factors in a cystic fibrosis (CF) cohort diagnosed by newborn screening and followed up to month 24.A prospective longitudinal multicenter study assessing nutritional status according to pancreatic status, feeding modalities, prescriptions, pulmonary outcome, and biological nutritional parameters.One hundred and five infants were recruited and 99 completed the study. Nutritional care management prevented undernutrition and stunting in those with exocrine pancreatic sufficiency (EPS), but affected (13/87) 15% and (21/86) 24%, respectively, of infants with exocrine pancreatic insufficiency (EPI). The logistic regression model found a positive association between both weight and length z scores "at risk" at month 24, and initial pulmonary symptoms (odds ratio [OR] 0.06, P 0.01 and OR 0.08, P 0.01, respectively); these symptoms were less frequent when age at first visit was earlier than 1.2 months (33% vs 67%, P = 0.02); stunting was also associated with high-calorie density intake and Staphylococcus aureus (OR 0.05, P = 0.01 and OR 0.17, P 0.01). Pulmonary outcome did not differ according to pancreatic status; breast-feeding for at least 3 months delayed first acquisition of Pseudomonas aeruginosa. Despite sodium and fat-soluble vitamin supplementation, half of both cohorts had low urinary sodium output and half of the EPI cohort had low vitamin D levels.Our data shed light on the fact that stunting was more frequent than undernutrition, while both parameters involved only patients with pancreatic insufficiency. Modalities of feeding were not associated with nutritional status; breast-feeding may provide some protection against acquisition of P aeruginosa.
Published: 2018

35. Optimized approach for the identification of highly efficient correctors of nonsense mutations in human diseases

Author: Philippe Reix, A. Prevotat, Séverine Amand, Dominique Hubert, Christine Bailly, Eric Adriaenssens, David Tulasne, Sara Gonzalez-Hilarion, Fabrice Lejeune, Hana Benhabiles, Sylvie Rebuffat, Mécanismes de tumorigenèse et thérapies ciblées, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plasticité Cellulaire et Cancer - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Lejeune, Fabrice
Subjects: 0301 basic medicine, Cystic Fibrosis, Pulmonology, RNA splicing, [SDV]Life Sciences [q-bio], Nonsense-mediated decay, Cultured tumor cells, Gene Expression, lcsh:Medicine, Biochemistry, Exon, Medicine and Health Sciences, lcsh:Science, media_common, Genetics, Multidisciplinary, Messenger RNA, Nonsense Mutation, Genomics, Enzymes, Nucleic acids, [SDV] Life Sciences [q-bio], Terminator (genetics), Genetic Diseases, Codon, Nonsense, Codon, Terminator, Cell lines, Oxidoreductases, Biological cultures, Luciferase, Research Article, media_common.quotation_subject, Nonsense, Nonsense mutation, Context (language use), Biology, Genome Complexity, 03 medical and health sciences, Autosomal Recessive Diseases, Humans, Genetic Predisposition to Disease, HeLa cells, RNA, Messenger, Clinical Genetics, Base Sequence, lcsh:R, Biology and Life Sciences, Proteins, Computational Biology, Cell cultures, Fibrosis, Introns, Nonsense Mediated mRNA Decay, Research and analysis methods, 030104 developmental biology, RNA processing, Mutation, Enzymology, RNA, lcsh:Q, Developmental Biology
Abstract: International audience; About 10% of patients with a genetic disease carry a nonsense mutation causing their pathology. A strategy for correcting nonsense mutations is premature termination codon (PTC) readthrough, i.e. incorporation of an amino acid at the PTC position during translation. PTCreadthrough-activating molecules appear as promising therapeutic tools for these patients. Unfortunately, the molecules shown to induce PTC readthrough show low efficacy, probably because the mRNAs carrying a nonsense mutation are scarce, as they are also substrates of the quality control mechanism called nonsense-mediated mRNA decay (NMD). The screening systems previously developed to identify readthrough-promoting molecules used cDNA constructs encoding mRNAs immune to NMD. As the molecules identified were not selected for the ability to correct nonsense mutations on NMD-prone PTC-mRNAs, they could be unsuitable for the context of nonsense-mutation-linked human pathologies. Here, a screening system based on an NMD-prone mRNA is described. It should be suitable for identifying molecules capable of efficiently rescuing the expression of human genes harboring a nonsense mutation. This system should favor the discovery of candidate drugs for treating genetic diseases caused by nonsense mutations. One hit selected with this screening system is presented and validated on cells from three cystic fibrosis patients.
Published: 2017

36. Acute chest pain in an adolescent with cystic fibrosis in September: Would you have thought about this?

Author: Philippe Reix, Florence Morfin-Sherpa, Hiba Dowaikh, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [GH Nord HCL, Lyon] (CNR des virus influenza), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Groupement Hospitalier Nord des HCL [Lyon], Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Nord des HCL [Lyon]-Institut des Agents Infectieux [Lyon] (IAI), and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Chest Pain, Adolescent, Cystic Fibrosis, education, Acute abdominal pain, Coxsackievirus Infections, Chest pain, medicine.disease_cause, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, medicine, Acute chest pain, Humans, In patient, Myositis, Bornholm, business.industry, enterovirus, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bornholm disease, Enterovirus B, Human, 3. Good health, Surgery, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Acute Disease, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Enterovirus, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Enterovirus B, business, myositis, Human
Abstract: International audience; Acute chest pain is common in patients with cystic fibrosis (CF). Here we report the case of an adolescent who suffered acute chest pain in September after an history of acute abdominal pain and fever. The reason for this clinical sceneriao was found to be Coxsackievirus B3, known to be responsible of Bornholm disease, a frequent but under recognized viral myositis. The diagnosis is mainly clinical, but evocating this diagnosis may avoid unnecessary exam.
Published: 2017

37. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial

Author: Laura A. Sass, Thomas Lahiri, Alicia Casey, Carlos Milla, James F. Chmiel, Fadi Asfour, Seth Walker, Alastair Reid, Jane C. Davies, Michael J. Rock, Xiaohong Huang, Barry Clements, Ronald C. Rubenstein, Tacjana Pressler, Philippe Reix, Anne Munck, Howard Schmidt, Timothy D. Starner, Doris Staab, Stephanie Bui, Christiane De Boeck, Melinda Solomon, Don S. Urquhart, Diana Quintero, Tim Lee, Gautham Marigowda, Fadel Ruiz, Margaret Rosenfeld, Floyd Livingston, Sanja Stanojevic, Matthias Griese, Anne Malfroot, Deborah Froh, Mark A. Chilvers, Isabelle Sermet Gaudelus, John McNamara, Sibylle Junge, Thomas G. Keens, Aaron Chidekel, Ian M. Balfour-Lynn, S. Tian, Claire E. Wainwright, Brian O'Sullivan, Susanna A. McColley, Christopher Hug, Philip Black, Lutz Naehrlich, Silke van Koningsburggen-Rietschel, Philip Robinson, John L. Colombo, Hiranjan Selvadurai, Felix Ratjen, George Z. Retsch-Bogart, Carlos E Milla, David M. Orenstein, David Schaeffer, Lena Hjelte, David Waltz, Alexandra G Cornell, Jodi Hilton, Larry C. Lands, Paul Robinson, Patrick A. Flume, Gary Mueller, Clinical sciences, and Growth and Development
Subjects: Male, Pediatrics, Cystic Fibrosis, Respiratory System, Aminopyridines, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, Cystic fibrosis, DISEASE, law.invention, Ivacaftor, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Forced Expiratory Volume, Surveys and Questionnaires, Clinical endpoint, 030212 general & internal medicine, Child, Chloride Channel Agonists, Sweat, Lung, ABNORMALITIES, Lumacaftor, INERT-GAS WASHOUT, Drug Combinations, Mucociliary Clearance, Female, Life Sciences & Biomedicine, CLINICAL-TRIALS, medicine.drug, Pulmonary and Respiratory Medicine, medicine.medical_specialty, YOUNG-CHILDREN, Placebo, LUNG CLEARANCE INDEX, 1117 Public Health and Health Services, 03 medical and health sciences, Critical Care Medicine, Double-Blind Method, General & Internal Medicine, medicine, Humans, Benzodioxoles, Adverse effect, Science & Technology, business.industry, 1103 Clinical Sciences, IN-VITRO, medicine.disease, PHE508DEL CFTR, CFTR POTENTIATOR, Clinical trial, 030228 respiratory system, chemistry, Mutation, VX14-809-109 investigator group, business, 1199 Other Medical and Health Sciences
Abstract: Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR. Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV 1) of 70 or more, and lung clearance index 2·5 (LCI 2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (
Published: 2017

38. Strong incidence of pseudomonas aeruginosa on bacterial rrs and ITS genetic structures of cystic fibrosis sputa

Author: Philippe Reix, François Vandenesch, Carine Commun, Hélène Meugnier, Isabelle Durieu, Laurence Pages-Monteiro, Benoit Cournoyer, Anne Doléans-Jordheim, Claire Bardel, Nolwenn Alliot, Jean Freney, Stéphane Durupt, Michele Perouse-de-Montclos, Romain Marti, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Laboratoire de Bactériologie, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bactériologie, Centre hospitalier Lyon Sud, Centre de Ressources et de Compétences (CRCM) adulte, Centre de ressources et Compétences (CRCM) enfant, Hopital Femme Mère Enfant, U851, Equipe de recherche Pathogènie des Staphylocoques, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Doleans-Jordheim, Anne, Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Institut d'Enseignement Supérieur et de Recherche en Alimentation, Santé Animale, Sciences Agronomiques et de l'Environnement, Hospices Civils de Lyon ( HCL ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Cystic Fibrosis, Pulmonology, lung-function, [SDV]Life Sciences [q-bio], lcsh:Medicine, medicine.disease_cause, Pathology and Laboratory Medicine, Polymerase Chain Reaction, law.invention, law, Antibiotics, RNA, Ribosomal, 16S, Prevotella, Medicine and Health Sciences, Cluster Analysis, stenotrophomonas-maltophilia, lcsh:Science, DNA extraction, Polymerase chain reaction, Multidisciplinary, biology, Antimicrobials, staphylococcus-aureus, Incidence, Microbiota, intergenic spacer analysis, microbial diversity, airway microbiota, pulmonary exacerbation, young-children, communities, pathogens, Pseudomonas Aeruginosa, Drugs, Genomics, 3. Good health, Anti-Bacterial Agents, Electrophoresis, Gel, Pulsed-Field, Bacterial Pathogens, Stenotrophomonas maltophilia, Medical Microbiology, Genetic Diseases, Stenotrophomonas, Neisseria, Research Article, DNA, Bacterial, 030106 microbiology, Haemophilus, Microbial Sensitivity Tests, Microbial Genomics, Microbiology, 03 medical and health sciences, Extraction techniques, Autosomal Recessive Diseases, Pseudomonas, Microbial Control, medicine, Genetics, Humans, Pseudomonas Infections, Microbial Pathogens, Pharmacology, Clinical Genetics, [ SDV ] Life Sciences [q-bio], Bacteria, Pseudomonas aeruginosa, lcsh:R, Sputum, Organisms, Genetic Variation, Biology and Life Sciences, biology.organism_classification, Fibrosis, Research and analysis methods, Burkholderia, RNA, Ribosomal, Antibiotic Resistance, lcsh:Q, Metagenomics, Microbiome, Antimicrobial Resistance, Developmental Biology
Abstract: Cystic fibrosis (CF) lungs harbor a complex community of interacting microbes, including pathogens like Pseudomonas aeruginosa. Meta-taxogenomic analysis based on V5-V6 rrs PCR products of 52 P. aeruginosa-positive (Pp) and 52 P. aeruginosa-negative (Pn) pooled DNA extracts from CF sputa suggested positive associations between P. aeruginosa and Stenotrophomonas and Prevotella, but negative ones with Haemophilus, Neisseria and Burkholderia. Internal Transcribed Spacer analyses (RISA) from individual DNA extracts identified three significant genetic structures within the CF cohorts, and indicated an impact of P. aeruginosa. RISA clusters Ip and IIIp contained CF sputa with a P. aeruginosa prevalence above 93%, and of 24.2% in cluster IIp. Clusters Ip and IIIp showed lower RISA genetic diversity and richness than IIp. Highly similar cluster IIp RISA profiles were obtained from two patients harboring isolates of a same P. aeruginosa clone, suggesting convergent evolution in the structure of their microbiota. CF patients of cluster IIp had received significantly less antibiotics than patients of clusters Ip and IIIp but harbored the most resistant P. aeruginosa strains. Patients of cluster IIIp were older than those of Ip. The effects of P. aeruginosa on the RISA structures could not be fully dissociated from the above two confounding factors but several trends in these datasets support the conclusion of a strong incidence of P. aeruginosa on the genetic structure of CF lung microbiota.
Published: 2017

39. 164 Are viral respiratory infections a real issue in infants with cystic fibrosis: preliminary results of a prospective cohort study

Author: Philippe Reix, S. Vrielynck, M. Perceval, F. Morfin, V. Jubin, Anne Doléans-Jordheim, M. Eymery, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), and Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pulmonary and Respiratory Medicine, 0303 health sciences, Pediatrics, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], medicine.disease, Cystic fibrosis, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Pediatrics, Perinatology and Child Health, medicine, Respiratory system, Prospective cohort study, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2017

40. Sensitivity and specificity of different methods for cystic fibrosis-related diabetes screening: is the oral glucose tolerance test still the standard?

Author: Laurent Remontet, Muriel Rabilloud, Behrouz Kassai-Koupai, Véronique Delaup, Philippe Reix, Stéphane Mazur, Gabriel Bellon, Catherine Mainguy, Tiphanie Ginoux, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Blood Glucose, Male, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Cystic fibrosis-related diabetes, 030209 endocrinology & metabolism, Comorbidity, Carbohydrate metabolism, Cystic fibrosis, Gastroenterology, Sensitivity and Specificity, Impaired glucose tolerance, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, Diabetes mellitus, Glucose Intolerance, medicine, Diabetes Mellitus, Prevalence, Humans, Mass Screening, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, ComputingMilieux_MISCELLANEOUS, Glycated Hemoglobin, business.industry, Glucose Tolerance Test, medicine.disease, Prognosis, 3. Good health, Pediatrics, Perinatology and Child Health, Female, France, Insulin Resistance, business, Biomarkers, Follow-Up Studies
Abstract: Background:Cystic fibrosis-related diabetes (CFRD) is a late cystic fibrosis (CF)-associated comorbidity whose prevalence is increasing sharply lifelong. Guidelines for glucose metabolism (GM) monitoring rely on the oral glucose tolerance test (OGTT). However, this test is neither sensitive nor specific. The aim of this study was to compare sensitivity and specificity of different methods for GM monitoring in children and adolescents with CF.Methods:Continuous glucose monitoring system (CGMS), used as the reference method, was compared with the OGTT, intravenous glucose tolerance test (IGTT), homeostasis model assessment index of insulin resistance (HOMA-IR), homeostasis model assessment index of β-cell function (HOMA-%B) and glycated haemoglobin AResults:Twenty-nine patients (median age: 13.1 years) were recruited. According to CGMS, 11 had DM, 12 IGT and six NGT, whereas OGTT identified three patients with DM and five with IGT. While 13 of 27 had insulin deficiency according to IGTT, there was 19 of 28 according to HOMA-%B. According to HOMA-IR, 12 of 28 had insulin resistance. HOMA-%B was the most sensitive method for CFRD screening [sensitivity 91% (95% CI), specificity 47% (95% CI) and negative predictive value 89% (95% CI)].Conclusions:OGTT showed the weak capacity to diagnose DM in CF and should no longer be considered as the reference method for CFRD screening in patients with CF. In our study, HOMA-%B showed promising metrics for CFRD screening. Finally, CGMS revealed that pathological glucose excursions were frequent even early in life.
Published: 2017

41. A simplified, semi-quantitative structural lung disease computed tomography outcome during quiet breathing in infants with cystic fibrosis

Author: Magali Saguintaah, R Gauthier, Philippe Reix, Ikram Taleb Arrada, Nicolas Molinari, Laure Couderc, Cécile Duboibaudry, Stefan Matecki, Muriel Le Bourgeois, Raphaël Chiron, Yann Cabon, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rouen] (CIC Rouen), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Charles Nicolle [Rouen], and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen
Subjects: Pulmonary and Respiratory Medicine, Lung Diseases, Male, medicine.medical_specialty, Concordance, Sedation, Chest tomography, Air trapping, Cystic fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Stage (cooking), Lung, ComputingMilieux_MISCELLANEOUS, Bronchiectasis, business.industry, Respiration, Reproducibility of Results, Infant, medicine.disease, 3. Good health, Surgery, medicine.anatomical_structure, Early Diagnosis, 030228 respiratory system, Lung disease, Research Design, Pediatrics, Perinatology and Child Health, Female, Radiology, medicine.symptom, business, Tomography, X-Ray Computed, Scoring
Abstract: International audience; Chest tomography (CT) using the controlled ventilation technique (CTCV) is a sensitive method to detect features of lung cystic fibrosis (CF) disease in infants with CF. However, this technique needs sedation and is not easily applied for the clinician who may need, in the follow-up, to evaluate more precisely lung disease in infants with CF. Thus, our study aims to evaluate if CT assessment of lung disease, without the need of sedation, during quiet breathing, using a semi-quantitative scoring system, is reproducible and may discriminate infants with CF from control infants at an early stage of the lung disease. 39 infants with CF underwent a first CT at 10.3 [9.4, 11.4] weeks of age. Among them, 33 underwent a second CT at 56.1 [53.1, 59.6] weeks of age. CF scoring images of the different scanner variables, i.e. bronchial wall thickening, bronchiectasis, mucus plugging and air trapping were compared to CT scoring obtained in 2 different groups of control infants of similar age without lung disease. Among all the constituents of the scoring, air trapping is the only parameter discriminating infants with CF from control infants at both ages in our study (p≤0.01). Moreover, air trapping explains 90% of the total score variability with r2=0.89 with a good concordance after re-scoring in blind, 6months apart, by the same operator for both infant populations: ICC=0.98 [0.97, 0.99]. In this study, we propose that CT during quiet breathing could be a useful clinical tool to evaluate the early presence of gas trapping in infants with CF.
Published: 2017

42. Lung clearance index: Evidence for use in clinical trials in cystic fibrosis

Author: Stefan Zielen, Judy Bradley, Cesare Braggion, Katherine O'Neill, H.G.M. Arets, K. De Boeck, Keith G. Brownlee, Diana Bilton, Katie J Bayfield, S. Lever, M. Le Bourgeois, J. A. Innes, Daniela Savi, Isabelle Sermet, Philippe Reix, Jane C. Davies, Lisa Kent, and Anders Lindblad
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Cystic Fibrosis, Lung Clearance Index, Severity of Illness Index, Cystic fibrosis, clinimetric properties, lung clearance index, multiple breath washout, outcome measures, surrogate endpoints, Outcome Assessment, Health Care, Clinical endpoint, Humans, Medicine, In patient, Pediatrics, Perinatology, and Child Health, Intensive care medicine, Randomized Controlled Trials as Topic, business.industry, Surrogate endpoint, Outcome measures, Reproducibility of Results, medicine.disease, Respiratory Function Tests, Clinical trial, Breath Tests, Lung disease, Pediatrics, Perinatology and Child Health, Physical therapy, Feasibility Studies, business, Biomarkers
Abstract: The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF. © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V.
Published: 2014

43. P273 Human papilloma virus vaccination among female patients attending the Auvergne-Rhône Alpes paediatric cystic fibrosis centres

Author: Philippe Reix, M. Perceval, C. Rousset-Jablonski, Isabelle Pin, Isabelle Durieu, C. Llerena, Quitterie Reynaud, S. Touzet, and A. Labbé
Subjects: Pulmonary and Respiratory Medicine, Human papilloma virus, Vaccination, Pediatrics, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, Female patient, Medicine, business, medicine.disease, Cystic fibrosis
Published: 2018

44. P034 Are patients with cystic fibrosis in clinical trials sensitive to the placebo effect? A metanalysis

Author: V. Veuillet, Behrouz Kassai-Koupai, François Gueyffier, Michel Cucherat, Philippe Reix, Julie Coton, Perrine Janiaud, and Ha-Hai Le
Subjects: Pulmonary and Respiratory Medicine, Clinical trial, medicine.medical_specialty, business.industry, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, business, Placebo, medicine.disease, Gastroenterology, Cystic fibrosis
Published: 2018

45. High incidence of non-tuberculous mycobacteria-positive cultures among adolescent with cystic fibrosis

Author: Raphaele Nove-Josserand, Zoe Cavalli, Philippe Reix, Isabelle Durieu, Quitterie Reynaud, Michèle Pérouse de Montclos, Stéphane Durupt, M. Perceval, Gerard Lina, and Romain Bricca
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Multivariate analysis, Adolescent, Cystic Fibrosis, Itraconazole, Mycobacterium Infections, Nontuberculous, Mycobacterium abscessus, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Respiratory Tract Infections, Univariate analysis, biology, business.industry, Incidence (epidemiology), Incidence, Case-control study, Nontuberculous Mycobacteria, bacterial infections and mycoses, medicine.disease, biology.organism_classification, Respiratory Function Tests, 030228 respiratory system, Case-Control Studies, Pediatrics, Perinatology and Child Health, Immunology, Female, France, Allergic bronchopulmonary aspergillosis, business, medicine.drug
Abstract: Background We evaluated the prevalence of non-tuberculous mycobacteria (NTM)-positive cultures among our cystic fibrosis (CF) center patients, reviewed risk factors for NTM positivity, and determined its impact on lung function evolution. Methods From 2009 to 2014, CF adults and children attending the CF center of Lyon (France) and having at least one positive NTM isolate were included. Each case was matched by age and gender with two CF patients with no NTM isolate (controls). Results 48 CF patients with NTM-positive isolates were matched to 96 controls. The age group for whom incident NTM was higher was young adolescents aged 13 to 17. A significant association for NTM positivity was found with Staphylococcus aureus in multivariate analysis and with allergic bronchopulmonary aspergillosis, corticosteroid and itraconazole in univariate analysis. Mean annual FEV1 decline was faster for NTM-positive patients compared to controls. Conclusion These data highlight the high incidence of NTM-positive cultures among young adolescents with CF.
Published: 2016

46. Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients

Author: Raphaële, Nové-Josserand, Soazic, Grard, Lila, Auzou, Philippe, Reix, Marlène, Murris-Espin, François, Brémont, Benyebka, Mammar, Laurent, Mely, Dominique, Hubert, Isabelle, Durieu, and Pierre-Régis, Burgel
Subjects: Adult, Male, Antifungal Agents, Adolescent, Cystic Fibrosis, Aspergillosis, Allergic Bronchopulmonary, Omalizumab, Immunoglobulin E, Middle Aged, Young Adult, Adrenal Cortex Hormones, Anti-Allergic Agents, Humans, Drug Therapy, Combination, Female, Child, Retrospective Studies
Abstract: Allergic bronchopulmonary aspergillosis (ABPA) affects up to 15% of patients with cystic fibrosis (CF). Corticosteroids are used as first-line therapy, but relapse and adverse effects commonly occur. Case reports have suggested the efficacy of the anti-IgE recombinant humanized monoclonal antibody omalizumab. A retrospective multicenter observational French study retrieved 32 CF patients (11 children and 21 adults) who have received omalizumab for more than 3 months in the context of ABPA. Clinical characteristics, concomitant medications (inhaled and oral corticosteroids, antifungal drugs), lung function, body mass index (BMI), and serum IgE were compared at the start and during the first year of omalizumab therapy. Omalizumab-related adverse effects and costs were also evaluated. No significant difference with omalizumab could be demonstrated with regard to lung function, BMI, or the number of patients receiving oral corticosteroids. At the time of initiation of omalizumab, 56% of patients were receiving oral corticosteroids. Five patients were able to discontinue corticosteroids during follow-up and nine patients were able to reduce their daily dose. A total of 78% of the patients had received antifungal therapy at the time of the initiation of omalizumab. Treatment tolerance was good (12.5% of patients experienced side effects). The median cost of omalizumab treatment was €3,620 per patient per month. Omalizumab may represent a steroid-sparing therapy in CF patients with ABPA. A randomized-controlled trial is urgently required to provide higher level of evidence regarding the efficacy and cost-effectiveness of omalizumab in CF patients with ABPA. Pediatr Pulmonol. 2017;52:190-197. © 2016 Wiley Periodicals, Inc.
Published: 2016

47. Moderate intake of docosahexaenoic acid raises plasma and platelet vitamin E levels in cystic fibrosis patients

Author: Stéphane Mazur, Michel Lagarde, Romain Colas, Véronique Delaup, Philippe Reix, Evelyne Véricel, Isabelle Durieu, Gabriel Bellon, Catherine Calzada, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Médecine Interne - Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Nice Sophia Antipolis - Faculté de Chirurgie Dentaire (UNS UFR Odontologie), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Service de Pneumologie Pédiatrique, Hospices Civils de Lyon (HCL)-Hôpital Debrousse, Inserm, Association 'Vaincre la mucoviscidose', Vericel, Evelyne, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)
Subjects: Adult, Blood Platelets, Male, 0301 basic medicine, medicine.medical_specialty, Antioxidant, Adolescent, Cystic Fibrosis, Docosahexaenoic Acids, genetic structures, medicine.medical_treatment, Clinical Biochemistry, Placebo, medicine.disease_cause, Cystic fibrosis, antioxidant status, Drug Administration Schedule, platelet lipid, Lipid peroxidation, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Double-Blind Method, Internal medicine, medicine, Humans, Vitamin E, oxidative stress, Child, plasma, Cross-Over Studies, business.industry, food and beverages, Cell Biology, docosahexaenoic acid, medicine.disease, 3. Good health, Thromboxane B2, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, Endocrinology, chemistry, Docosahexaenoic acid, lipids (amino acids, peptides, and proteins), Lipid Peroxidation, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress
Abstract: International audience; Patients with cystic fibrosis have increased oxidative stress and impaired antioxidant systems. Moderate intake of docosahexaenoic acid (DHA) may favor the lowering of oxidative stress. In this randomized, double-blind, cross-over study, DHA or placebo capsules, were given daily to 10 patients, 5 mg/kg for 2 weeks then 10 mg/kg DHA for the next 2 weeks (or placebo). After 9 weeks of wash-out, patients took placebo or DHA capsules. Biomarkers of lipid peroxidation and vitamin E were measured at baseline, and after 2 and 4 weeks of treatment in each phase. The proportions of DHA increased both in plasma and platelet lipids after DHA supplementations. The lipid peroxidation markers did not significantly decrease, in spite of a trend, after the first and/or the second dose of DHA but plasma and platelet vitamin E amounts increased significantly after DHA supplementation. Our findings reinforce the antioxidant potential of moderate DHA intake in subjects displaying increased oxidative stress.
Published: 2016

48. Is the raised volume rapid thoracic compression technique ready for use in clinical trials in infants with cystic fibrosis?

Author: Isabelle Sermet, Judy Bradley, Stefan Matecki, Lisa Kent, Stephanie D. Davis, Stefan Zielen, Kris De Boeck, Hubertus G.M. Arets, Philippe Reix, Cesare Braggion, Muriel Le Bourgeois, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Health and Rehabilitation Sciences Research Institute, University of Ulster, University of Ulster, Newtownabbey, University of Leuven Medical School, University Hospitals KULeuven, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), J.W. Goethe Universität, Institut für Geowissenschaften, Altenhöferallee 1, D-60438 Frankfurt am Main, Germany, Anna Meyer Children's Hospital Florence, University of Florence, University Medical Center [Utrecht], Belfast Health and Social Care Trust, Cystic Fibrosis Pediatric Centre, Indianapolis, Centre de recherche Croissance et signalisation (UMR_S 845), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Firenze = University of Florence (UniFI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and MORNET, Dominique
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Standardization, [SDV]Life Sciences [q-bio], Context (language use), Review, Pediatrics, Cystic fibrosis, Surrogate outcome, 03 medical and health sciences, 0302 clinical medicine, Primary outcome, Clinical trials, Outcome Assessment, Health Care, medicine, Journal Article, Humans, 030212 general & internal medicine, Raised volume rapid thoracic compression, Pediatrics, Perinatology, and Child Health, Societies, Medical, Clinical Trials as Topic, Surrogate endpoint, business.industry, Patient Acuity, Infant, medicine.disease, Perinatology, Respiratory Function Tests, 3. Good health, [SDV] Life Sciences [q-bio], Europe, and Child Health, Natural history, Clinical trial, 030228 respiratory system, Reference values, Pediatrics, Perinatology and Child Health, Physical therapy, business, Infant pulmonary function, Clinimetric properties
Abstract: The European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) has established a Standardization Committee to undertake a rigorous evaluation of promising outcome measures with regard to use in multicentre clinical trials in cystic fibrosis (CF). The aim of this article is to present a review of literature on clinimetric properties of the infant raised-volume rapid thoracic compression (RVRTC) technique in the context of CF, to summarise the consensus amongst the group on feasibility and answer key questions regarding the promotion of this technique to surrogate endpoint status. Methods A literature search (from 1985 onwards) identified 20 papers that met inclusion criteria of RVRTC use in infants with CF. Data were extracted and tabulated regarding repeatability, validity, correlation with other outcome measures, responsiveness and reference values. A working group discussed the tables and answered 4 key questions. Results Overall, RVRTC in particular forced expiratory volume in 0.5s, showed good clinimetric properties despite presence of individual variability. Few studies showed a relationship between RVRTC and inflammation and infection, and to date, data remains limited regarding the responsiveness of RVRTC after an intervention. Concerns were raised regarding feasibility in multi-centre studies and availability of reference values. Conclusion The ECFS-CTN Working Group considers that RVRTC cannot be used as a primary outcome in clinical trials in infants with CF before universal standardization of this measurement is achieved and implementation of inter-institutional networking is in place. We advise its use currently in phase I/II trials and as a secondary endpoint in phase III studies. We emphasise the need for (1) more short-term variability and longitudinal ‘natural history' studies, and (2) robust reference values for commercially available devices.
Published: 2016

49. EPS1.4 Real life acute changes in spirometric indices after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis

Author: A. Labaste, M.-C. Werck-Gallois, A. Toutain-Rigolet, Philippe Reix, Laurianne Coutier, S. Vrielynck, M. Perceval, Catherine Mainguy, and V. Jubin
Subjects: Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, business.industry, Lumacaftor, medicine.disease, Cystic fibrosis, Ivacaftor, chemistry.chemical_compound, chemistry, Pediatrics, Perinatology and Child Health, medicine, business, Intensive care medicine, medicine.drug
Published: 2017

50. Clinical Phenotype and Genotype of Children with Borderline Sweat Test and Abnormal Nasal Epithelial Chloride Transport

Author: Stéphanie Bui, Thierry Bienvenu, Philippe Reix, Gabriel Bellon, Emanuelle Girodon, E. Deneuville, Isabelle Sermet-Gaudelus, Nathalie Stremmler, Albert Iron, Veronika Skalická, Michel Roussey, F. Huet, Delphine Roussel, Gérard Lenoir, M. Lebourgeois, V. Vavrova, Dorota Sands, Milan Macek, Aleksander Edelman, Jacques Sarles, Anne Munck, and Isabelle Fajac
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pathology, Pancreatic disease, Adolescent, Cystic Fibrosis, Genotype, DNA Mutational Analysis, Cystic Fibrosis Transmembrane Conductance Regulator, Critical Care and Intensive Care Medicine, Cystic fibrosis, Gastroenterology, SWEAT, Chlorides, Predictive Value of Tests, Intensive care, Internal medicine, medicine, Humans, Child, Sweat, Sweat test, biology, medicine.diagnostic_test, business.industry, Respiratory disease, Infant, Reproducibility of Results, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Nasal Mucosa, Phenotype, Case-Control Studies, biology.protein, business, Biomarkers
Abstract: The diagnosis of cystic fibrosis (CF) is based on a characteristic clinical picture in association with a sweat chloride (Cl(-)) concentration greater than 60 mmol/L or the identification of two CF-causing mutations. A challenging problem is the significant number of children for whom no definitive diagnosis is possible because they present with symptoms suggestive of CF, a sweat chloride level in the intermediate range between 30 and 60 mmol/L, and only one or no identified CF-causing mutation.To investigate the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways of children with intermediate sweat tests and inconclusive genetic findings in correlation with clinical phenotype and genotype.We developed a composite nasal potential difference (NPD) diagnostic score to discriminate patients with CF from non-CF patients. We tested NPD in 50 children (age, 6 mo to 18 yr) with equivocal diagnoses and correlated the NPD diagnostic score with clinical phenotypes and genotypes.Fifteen of the 50 children had NPD scores in the CF range. Eight of the 15 carried two CFTR mutations compared with only 5 of the 35 children with normal NPD scores (P = 0.01). They were significantly younger at evaluation and had recurrent lower respiratory tract infections, chronic productive coughs, and chronic Staphylococcus aureus colonization significantly more often than the 35 children with normal NPD results.Evaluation of CFTR function in the nasal epithelium of children with inconclusive CF diagnoses can be a useful diagnostic tool and help clinicians to individualize therapeutic strategy.
Published: 2010

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