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1. Rapid Improvement after Starting Elexacaftor–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease

Author: Pierre-Régis Burgel, Isabelle Durieu, Raphaël Chiron, Sophie Ramel, Isabelle Danner-Boucher, Anne Prevotat, Dominique Grenet, Christophe Marguet, Martine Reynaud-Gaubert, Julie Macey, Laurent Mely, Annlyse Fanton, Sébastien Quetant, Lydie Lemonnier, Jean-Louis Paillasseur, Jennifer Da Silva, Clémence Martin, Claire Andrejak, Arnaud Becourt, Julie Mounard, Claire Poulet, Cinthia Rames, Marie Talleux, Marie-Chantal Chevalier, Estelle Darviot, Marie Jouvenot, Caroline Marien, Audrey Paris, Cécile Pelatan, Christine Person, Pascaline Priou, Françoise Troussier, Thierry Urban, Marie-Laure Dalphin, Jean-Charles Dalphin, Alice Ladaurade, Didier Pernet, Bénédicte Richaud-Thiriez, Pauline Roux-Claude, Nathalia Blanc, Vincent Boisserie-Lacroix, Stephanie Bui, Cyrielle Collet, Stéphane Debelleix, Emmanuel Bergot, Jacques Brouard, Karine Campbell, Muriel Laurans, Virginie Ribault, Corinne Borderon, Marie-Christine Heraud, Guillaume Labbe, Sylvie Montcouquiol, Isabelle Petit, Marc Ruivard, Céline Delestrain, Benoit Douvry, Ralph Epaud, Bernard Maitre, Natascha Remus, Guillaume Beltramo, Anne Houzel, Frédéric Huet, Stéphanie Perez, Amale Boldron-Ghaddar, Manuela Scalbert, Rabah Bouzioukh, Charles Simon, Boubou Camara, Rébecca Hamidfar, Catherine Llerena, Isabelle Pin, Antoine Deschildre, Alice Gicquello, Olivier Le Rouzic, Clara Leroy, Nicolas Paris, Thierry Perez, Caroline Thumerelle, Dominique Turck, Nathalie Wizla, Magali Dupuy-Grasset, Jane Languepin, Alexandra Masson-Rouchaud, Céline Menetrey, Stéphane Durupt, Sophie L’Excellent, Raphaele Nove-Josserand, Camille Ohlmann, Phillipe Reix, Quitterie Reynaud, Marie-Christine Werck-Gallois, Mélissandre Baravalle, Bérangère Coltey, Nadine Desmazes-Dufeu, Jean-Christophe Dubus, Clarisse Gautier, Jean-Baptiste Rey, Nathalie Stremler, Davide Caimmi, Margot Devrait, Johan Moreau, Yves Billon, Aurore Blondé, Anne Guillaumot, Sébastien Kiefer, Laura Peretti, Aurélie Tatopoulos, Angélica Tiotiu, Myriam Benhamida, Tiphaine Bihouee, Emmanuel Eschapasse, Adrien Tissot, Marie Giannantonio, Sylvie Leroy, Carole Piccini-Bailly, Johana Pradelli, Jonathan Messika, Véronique Boussaud, Nicolas Carlier, Isabelle Honoré, Dominique Hubert, Reem Kanaan, Céline Bailly-Botuha, Frédérique Chedevergne, Jacques De Blic, Christophe Delacourt, David Drummond, Brigitte Fauroux, Chantal Karila, Muriel Le Bourgeois, Isabelle Sermet, Bertrand Delaisi, Michèle Gerardin, Veronique Houdouin, Laurence Leclainche, Guillaume Aubertin, Laura Berdah, Annick Clement, Harriet Corvol, Nadia Nathan, Blandine Prevost, Nicolas Richard, Aline Tamalet, Jessica Taytard, Guillaume Thouvenin, Barbara Tourniaire, Michel Abely, Katia Bessaci-Kabouya, Sandra Dury, Bruno Ravoninjatovo, Alain Dabadie, Michel Dagorne, Eric Deneuville, Marie Jamin, Mélanie Ribault, Clémentine Vigier, Chantal Belleguic, Graziella Brinchault, Benoit Desrues, Audrey Barzic, Anne Dirou-Prigent, Jean Le Bihan, Krista Revert, Thomas Ropars, Laure Couderc, Stéphane Dominique, Hélène Morisse-Pradier, Stéphanie Pramil, Luc Thiberville, Nathalie Allou, Laurent Enaud, Elsa Gachelin, Eric Huchot, Annabelle Payet, Caroline Perisson, Saguiraly Piyaraly, Sophie Valois, Audrey Herzog, Romain Kessler, Michele Porzio, Laurence Weiss, Laurence Beaumont, Olivier Brugiere, Sylvie Colin, de Verdiere, Elise Cuquemelle, Sandra De Miranda, Adbdul Monem Hamid, François Parquin, Clément Picard, Antoine Roux, Charlotte Roy, François Bremont, Alain Didier, Marion Dupuis, Guillaume Faviez, Géraldine Labouret, Marie Mittaine, Marlène Murris-Espin, Léa Roditis, Laure Cosson, Patrice Diot, Thomas Flament, Charlotte Giraut, Julie Mankikian, Baptiste Arnouat, Gaétane Mousset, Véronique Storni, Philippe Vigneron, Emmanuelle Coirier-Duet, Asma Gabsi, 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), Université de Lyon, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Fondation ILDYS (ILDYS), Institut du Thorax [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Foch [Suresnes], CHU Rouen, Normandie Université (NU), INSERM-TRANSFERT [Paris] (IT), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Hôpital Nord [CHU - APHM], Aix Marseille Université (AMU), CHU Bordeaux [Bordeaux], Hôpital Renée Sabran [CHU - HCL], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire [Grenoble] (CHU), Vaincre la Mucoviscidose, Association de lutte contre la Mucoviscidose, EFFI-STAT, URC/CIC Paris Descartes Necker Cochin, Hôpital Necker, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Supported by Vaincre la Mucoviscidose, Fondation Sauver la Vie, Universite Paris Descartes, Filiere Maladies Rares Muco-CFTR, and Legs PascalBonnet., Participating Investigators of the FrenchCystic Fibrosis Reference Network StudyGroup:Claire Andrejak, Arnaud Becourt, JulieMounard, Claire Poulet, Cinthia Rames, MarieTalleux (Amiens), Marie-Chantal Chevalier,Estelle Darviot, Marie Jouvenot, Caroline Marien,Audrey Paris, C ecile Pelatan, Christine Person,Pascaline Priou, Franc ̧oise Troussier, ThierryUrban (Angers-Le Mans), Marie-Laure Dalphin,Jean-Charles Dalphin, Alice Ladaurade, DidierPernet, B en edicte Richaud-Thiriez, PaulineRoux-Claude (Besanc ̧on), Nathalia Blanc,Vincent Boisserie-Lacroix, Stephanie Bui,Cyrielle Collet, St ephane Debelleix, Julie Macey(Bordeaux), Emmanuel Bergot, JacquesBrouard, Karine Campbell, Muriel Laurans,Virginie Ribault (Caen), Corinne Borderon,Marie-Christine Heraud, Guillaume Labbe,SylvieMontcouquiol, Isabelle Petit, Marc Ruivard(Clermont-Ferrand), C eline Delestrain, BenoitDouvry, Ralph Epaud, Bernard Maitre, NataschaRemus (Cr eteil), Guillaume Beltramo, AnnlyseFanton, Anne Houzel, Fr ed eric Huet, St ephaniePerez (Dijon), AmaleBoldron-Ghaddar, ManuelaScalbert (Dunkerque), Rabah Bouzioukh,Laurent Mely, Charles Simon (Giens), BoubouCamara, R ebecca Hamidfar, Catherine Llerena,Isabelle Pin, S ebastien Quetant (Grenoble), Antoine Deschildre, Alice Gicquello, Olivier LeRouzic, Clara Leroy, Nicolas Paris, Thierry Perez,Anne Prevotat, Caroline Thumerelle, DominiqueTurck, Nathalie Wizla (Lille), Magali Dupuy-Grasset, Jane Languepin, Alexandra Masson-Rouchaud, C eline Menetrey (Limoges), IsabelleDurieu, St ephane Durupt, Sophie L’Excellent,Raphaele Nove-Josserand, Camille Ohlmann,Phillipe Reix, Quitterie Reynaud, Marie-ChristineWerck-Gallois (Lyon), M elissandre Baravalle,B erang ere Coltey, Nadine Desmazes-Dufeu,Jean-Christophe Dubus, Clarisse Gautier, Jean-Baptiste Rey, Martine Reynaud-Gaubert,Nathalie Stremler (Marseille), Davide Caimmi,Rapha€el Chiron, Margot Devrait, Johan Moreau(Montpellier), Yves Billon, Aurore Blond e, AnneGuillaumot, S ebastien Kiefer, Laura Peretti,Aur elie Tatopoulos, Ang elica Tiotiu (Nancy), Myriam Benhamida, Tiphaine Bihouee, IsabelleDanner-Boucher, Emmanuel Eschapasse,Adrien Tissot (Nantes), Marie Giannantonio,Sylvie Leroy, Carole Piccini-Bailly, JohanaPradelli (Nice), Jonathan Messika (Paris, Bichat), V eronique Boussaud, Pierre-R egis Burgel,Nicolas Carlier, Isabelle Honor e, DominiqueHubert, Reem Kanaan, Cl emence Martin (Paris,Cochin), C eline Bailly-Botuha, Fr ed eriqueChedevergne, Jacques De Blic, ChristopheDelacourt, David Drummond, Brigitte Fauroux,Chantal Karila, Muriel Le Bourgeois, IsabelleSermet (Paris, Necker), Bertrand Delaisi,Mich ele Gerardin, Veronique Houdouin,Laurence Leclainche (Paris, Robert Debr e), Guillaume Aubertin, Laura Berdah, AnnickClement, Harriet Corvol, Nadia Nathan, BlandinePrevost, Nicolas Richard, Aline Tamalet, JessicaTaytard, Guillaume Thouvenin, BarbaraTourniaire (Paris, Trousseau), Michel Abely,Katia Bessaci-Kabouya, Sandra Dury, BrunoRavoninjatovo (Reims), Alain Dabadie, MichelDagorne, Eric Deneuville, Marie Jamin, M elanieRibault, Cl ementine Vigier (Rennes – SaintBrieuc), Chantal Belleguic, Graziella Brinchault,Benoit Desrues (Rennes), Audrey Barzic, AnneDirou-Prigent, Jean Le Bihan, Sophie Ramel,Krista Revert, Thomas Ropars (Roscoff), LaureCouderc, St ephane Dominique, ChristopheMarguet, H el ene Morisse-Pradier, St ephaniePramil, Luc Thiberville (Rouen), Nathalie Allou,Laurent Enaud, Elsa Gachelin, Eric Huchot,Annabelle Payet, Caroline Perisson, SaguiralyPiyaraly, Sophie Valois (La R eunion), AudreyHerzog, Romain Kessler, Michele Porzio,Laurence Weiss (Strasbourg), LaurenceBeaumont, Olivier Brugiere, Sylvie Colin deVerdiere, Elise Cuquemelle, Sandra De Miranda,Dominique Grenet, Adbdul Monem Hamid,Franc ̧ois Parquin, Cl ementPicard, Antoine Roux,Charlotte Roy (Suresnes), Franc ̧ois Bremont,Alain Didier, Marion Dupuis, Guillaume Faviez,G eraldine Labouret, Marie Mittaine, Marl eneMurris-Espin, L ea Roditis (Toulouse), LaureCosson, Patrice Diot, Thomas Flament, CharlotteGiraut, JulieMankikian(Tours), Baptiste Arnouat,Ga etane Mousset, V eronique Storni, PhilippeVigneron (Vannes-Lorient), and Emmanuelle Coirier-Duet, and Asma Gabsi (Versailles)
Subjects: Lung Diseases, Male, elexacaftor, Indoles, Cystic Fibrosis, Pyridines, medicine.medical_treatment, Regulator, Aminophenols, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cystic fibrosis, Gastroenterology, Membrane Potentials, Ivacaftor, 0302 clinical medicine, Prospective Studies, 030212 general & internal medicine, Chloride Channel Agonists, Aged, 80 and over, Middle Aged, Transmembrane protein, Drug Combinations, Quinolines, Female, France, medicine.drug, Adult, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, cystic fibrosis transmembrane conductance regulator modulators, Adolescent, Pulmonary disease, Young Adult, 03 medical and health sciences, Internal medicine, lung transplantation, medicine, Humans, Lung transplantation, In patient, Aged, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Editorials, medicine.disease, 030228 respiratory system, Tezacaftor, Pyrazoles, business
Abstract: International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)
Published: 2021
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2. Risk factors for Pseudomonas aeruginosa airway infection and lung function decline in children with cystic fibrosis

Author: Astrid Kemgang, Pierre-Yves Boëlle, Harriet Corvol, Manon Ruffin, Julie Mésinèle, and Loïc Guillot
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung, Proportional hazards model, business.industry, Pseudomonas aeruginosa, medicine.disease, medicine.disease_cause, Cystic fibrosis, Gastroenterology, Confidence interval, Liver disease, medicine.anatomical_structure, Internal medicine, Diabetes mellitus, Pediatrics, Perinatology and Child Health, Epidemiology, medicine, business
Abstract: Background Cystic fibrosis (CF) lung disease is characterised by recurrent Pseudomonas aeruginosa (Pa) infections, leading to structural lung damage and decreased survival. The epidemiology of Pa infection and its impact on lung function in people with CF (pwCF), especially in recent birth cohorts, remain uncertain. Methods We included 1,231 French pwCF under 18 years of age. Age at initial acquisition (Pa-IA), chronic colonisation (Pa-CC), and duration from Pa-IA to Pa-CC were estimated using the Kaplan-Meier method. Demographic, clinical, and genetic characteristics were analysed as risk factors for Pa infection using Cox regression models. Lung function decline was assessed by modelling percent-predicted forced expiratory volume in 1 s (ppFEV1) before Pa infection, after Pa-IA, and after Pa-CC. Results Among the 1,231 pwCF, 50% had Pa-IA by the age of 5.1 years [95% confidence interval (CI) 3.8-6.2] and 25% had Pa-CC by the age of 14.7 years (95% CI 12.1 to ∞). We observed that CF-related diabetes and liver disease were risk factors for Pa, while gender, CFTR variants, and CF centre size were not. Genetic variants of TNF, DCTN4, SLC9A3, and CAV2 were confirmed to be associated with Pa. The annual rate of ppFEV1 decline before Pa was -0.38% predicted/year (95% CI -0.59 to -0.18), which decreased significantly after Pa-IA to -0.93% predicted/year (95% CI -1.14 to -0.71) and after Pa-CC to -1.51% predicted/year (95% CI -1.86 to -1.16). Conclusions We identified and replicated several risk factors associated with Pa infection and showed its deleterious impact on lung function in young pwCF. This large-scale study confirmed that Pa airway infection is a major determinant of lung disease severity.
Published: 2022
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3. Cystic fibrosis–related diabetes onset can be predicted using biomarkers measured at birth

Author: Emmanuelle Brochiero, Pearce G. Wilcox, Lara Bilodeau, Mays Merjaneh, Nancy Morrison, Lisa J. Strug, Angela Hillaby, Julie Avolio, Katherine Keenan, Lynda Lazosky, Jennifer Itterman, Michael D. Parkins, Émilie Maille, Naim Panjwani, Mark A. Chilvers, Lei Sun, Jennifer Pike, Richard van Wylick, Yu Chung Lin, Raquel Consunji-Araneta, Caroline Burgess, Lorna Kosteniuk, Lori Fairservice, Christine Donnelly, Natalie Henderson, Damien Adam, Scott M. Blackman, Dimas Mateos-Corral, Bradley S. Quon, Mary Jackson, Janna Brusky, Felix Ratjen, Elizabeth Tullis, Garry R. Cutting, Clare Smith, Melinda Solomon, Harriet Corvol, Valerie Levesque, Daniel Hughes, Fan Lin, Nathalie Vadeboncoeur, Candice Bjornson, Yves Berthiaume, Guillaume Côté-Maurais, Anne L. Stephenson, Winnie Leung, Shaikh Iqbal, Jiafen Gong, Johanna M. Rommens, Mary Jane Smith, Paula Barrett, Joe Reisman, Terry Viczko, Katie Griffin, Danny Veniott, Vanessa McMahon, Stéphanie Bégin, April Price, Emma Karlsen, and Andrea Dale
Subjects: Oncology, medicine.medical_specialty, business.industry, Trypsinogen, Cystic fibrosis-related diabetes, Prevalence, medicine.disease, Cystic fibrosis, Article, Human genetics, chemistry.chemical_compound, chemistry, Disease severity, Diabetes mellitus, Internal medicine, Medicine, business, Genetics (clinical), Genetic association
Abstract: Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.
Published: 2021
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4. Severe central apnea secondary to cerebellar dysplasia in a child: look past Joubert syndrome

Author: Guillaume Aubertin, Chiara Sileo, Diana Rodriguez, Harriet Corvol, Stéphanie Valence, Nicole Beydon, Jessica Taytard, Plamen Bokov, Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie [CHU Trousseau], 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), AP-HP Hôpital universitaire Robert-Debré [Paris], 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], Service de physiologie, unité fonctionnelle d’explorations respiratoires [CHU Trousseau], Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Mucoviscidose: physiopathologie et phénogénomique [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: MESH: Kidney Diseases, Cystic, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, MESH: Abnormalities, Multiple, Central sleep apnea, Cerebellar dysplasia, Central apnea, Case Reports, Polysomnography, Tachypnea, central sleep apnea, Joubert syndrome, MESH: Magnetic Resonance Imaging, children, MESH: Child, Female patient, medicine, MESH: Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Humans, medicine.diagnostic_test, business.industry, MESH: Retina, medicine.disease, MESH: Eye Abnormalities, Sleep in non-human animals, MESH: Cerebellum, respiratory tract diseases, 3. Good health, Neurology, MESH: Sleep Apnea, Central, cerebellar dysplasia, Neurology (clinical), medicine.symptom, business, MESH: Female, tachypnea, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: We report the case of a female patient aged 12 years referred to our pediatric sleep unit with a history of central sleep apnea associated with transient episodes of tachypnea on polysomnography recordings. The patient was otherwise healthy, with no personal or family medical history, and had a normal physical and neuropsychological examination. Brain magnetic resonance imaging showed signs of cerebellar vermis dysplasia but without the classical features of the molar tooth sign. The rest of the workup (genetic tests, blood tests, cardiac investigations) was normal except for an increased peripheral chemosensitivity to carbon dioxide and oxygen. The patient was successfully treated with bilevel positive airway pressure. This case report highlights the importance of performing brain magnetic resonance imaging in patients with central sleep apnea to study the cerebellum, beyond the brainstem area. Cerebellar malformations can be found even in the absence of any other neurological condition. CITATION: Taytard J, Valence S, Sileo C, et al. Severe central apnea secondary to cerebellar dysplasia in a child: look past Joubert syndrome. J Clin Sleep Med. 2020;16(12):2113–2116.
Published: 2020
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5. SLC6A14, un gène modificateur dans la mucoviscidose

Author: Julie Mésinèle, Julia Mercier, Loïc Guillot, Manon Ruffin, Claire Calmel, Harriet Corvol, 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), Service de Pneumologie pédiatrique [CHU Trousseau], and CHU Trousseau [APHP]
Subjects: Pulmonary and Respiratory Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Monogenic disease, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Medicine, In patient, 030212 general & internal medicine, Mucoviscidose, Gene, Lung function, business.industry, respiratory system, medicine.disease, Phenotype, Modifier genes, respiratory tract diseases, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030228 respiratory system, Immunology, Infection, business, SLC6A14, Gènes modificateurs, Modifier Genes
Abstract: International audience; Although cystic fibrosis is a monogenic disease, a considerable clinical phenotypic variability is observed in patients with the same CFTR mutations. Thanks to the development of new and powerful tools for carrying out genetic studies, several genes called “modifier genes” have been identified as being associated with the severity of the lung function disorder in cystic fibrosis patients. Among these genes, SLC6A14 may modulate the anti-infective response and epithelial integrity of the airways, thus providing a potential therapeutic target to improve the patient's lung function.; Bien que la mucoviscidose soit une maladie monogénique, une diversité phénotypique considérable est observée chez des patients portant les mêmes mutations de CFTR. Grâce au développement d’outils nouveaux et puissants pour la réalisation d’études génétiques, de nombreux gènes appelés « gènes modificateurs » ont été découverts comme étant associés à la sévérité de l’atteinte pulmonaire chez les patients atteints de mucoviscidose. Parmi ces gènes, le gène SLC6A14 pourrait moduler la réponse anti-infectieuse et l’intégrité de l’épithélium des voies aériennes, constituant ainsi une cible thérapeutique potentielle pour améliorer la fonction respiratoire des patients.
Published: 2020
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6. Nocturnal hypoventilation in Down syndrome children with or without sleep apnea

Author: Nicole Beydon, Guillaume Aubertin, Jessica Taytard, Nicolas Richard, Laura Berdah, Harriet Corvol, Taytard, Jessica, Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Male, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], obstructive sleep apnea syndrome, Comorbidity, Polysomnography, Sleep medicine, nocturnal hypoventilation, children, Respiratory muscle, Humans, Medicine, Oximetry, Child, Retrospective Studies, Sleep Apnea, Obstructive, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, Sleep apnea, Hypoventilation, Carbon Dioxide, medicine.disease, respiratory tract diseases, [SDV] Life Sciences [q-bio], Obstructive sleep apnea, Pulse oximetry, Apnea–hypopnea index, Case-Control Studies, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Down Syndrome, medicine.symptom, business
Abstract: International audience; Background: There is a high prevalence of obstructive sleep apnea (OSA) in children with Down syndrome (DS), sometimes associated with alveolar hypoventilation.Objective: To compare transcutaneous partial pressure of carbon dioxide (PtcCO2 ) and pulse oximetry (SpO2 ) in children with DS and in control children with OSA.Patients and methods: This retrospective case-control study involved children followed in Trousseau Hospital (Paris) Sleep Center. Polysomnography (PSG) recordings and clinical files of children with DS were reviewed to identify clinical signs of OSA and comorbidities associated with DS. Controls were children who presented with OSA of ENT origin without other comorbidities (exceptions: two overweight, one obese, and three with well-controlled asthma). DS subjects and controls were matched for age and apnea hypopnea index.Results: There were 28 children in each group. Mean PtcCO2 during sleep was significantly higher in patients with DS compared to controls (44 mm Hg vs 42 mm Hg, P = .001). Five (21%) patients with DS met the American Academy of Sleep medicine criteria for hypoventilation, compared to one (4%) in the control group. The mean PtcO2 during sleep was significantly lower in patients with DS (77 mm Hg vs 82 mm Hg, P = .003).Conclusions: This is the first study to compare nocturnal gas exchange in children with DS to a control group of children with similar OSA. Our data demonstrate that children with DS have increased PtcCO2 regardless of the presence of OSA and its severity. This may be due to respiratory muscle hypotonia and/or ventilatory control alteration in patients with DS.
Published: 2020
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7. SLC6A14 Impacts Cystic Fibrosis Lung Disease Severity via mTOR and Epithelial Repair Modulation

Author: Elisabeth Longchampt, Julia Mercier, Claire Calmel, Loïc Guillot, Fatiha Merabtene, Erika N. Sutanto, Edouard Sage, Harriet Corvol, Pierre-Yves Boëlle, Julie Mésinèle, Anthony Kicic, Manon Ruffin, HAL UVSQ, Équipe, 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), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), The University of Western Australia (UWA), Curtin University [Perth], Planning and Transport Research Centre (PATREC), Hôpital Foch [Suresnes], Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Mucoviscidose: physiopathologie et phénogénomique [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), RF20170501936, RF20180502243, RF20190502451, JM received a doctoral fellowship from the French Ministry of Higher Education, Research and Innovation. MR received a post-doctoral fellowship from the French cystic fibrosis non-profit organization Vaincre la mucoviscidose (RF20180502243 and RF20190502451). LG received a grant from the French cystic fibrosis non-profit organization Vaincre la mucoviscidose (RF20170501936, RF20180502243, and RF20190502451)., CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Perth Children's Hospital [Nedlands, WA, Australia]
Subjects: business.industry, [SDV]Life Sciences [q-bio], lung function, respiratory system, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Cystic fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, respiratory tract diseases, amino acid transporter, cystic fibrosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Lung disease, modifier genes, medicine, Cancer research, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, Molecular Biology, PI3K/AKT/mTOR pathway, bronchial epithelial cells, SLC6A14
Abstract: Cystic fibrosis (CF), due to pathogenic variants in CFTR gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 promoter activity using a luciferase reporter and the role of SLC6A14 in the mechanistic target of rapamycin kinase (mTOR) signaling pathway and airway epithelial repair. We confirm that SLC6A14 rs3788766 SNP is associated with lung disease severity in pwCF (p = 0.020; n = 3,257, pancreatic insufficient, aged 6–40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation, and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that SLC6A14 genotype might affect lung disease severity of people with cystic fibrosis via mTOR and epithelial repair mechanism modulation in the lung.
Published: 2022
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8. Factors for severe outcomes following SARS-CoV-2 infection in people with cystic fibrosis in Europe

Author: Isabelle Fajac, Egil Bakkeheim, Halyna Makukh, Tsitsino Parulava, Jacqui G. van Rens, A. Fox, Luísa Pereira, A. Zolin, Hanne Vebert Olesen, Panayiotis K. Yiallouros, Damian G. Downey, Carla Colombo, Elpis Hatziagorou, Andreas Jung, Harriet Corvol, Pavel Drevinek, Liviu Pop, Elena Kondratyeva, Géraldine Daneau, Irena Kasmi, Siobhán B. Carr, Vincent Gulmans, Rebecca Cosgriff, Edward F. McKone, Lukasz Woźniacki, Satenik Harutyunyan, Andrea Dugac Vukic, Annalisa Orenti, Lutz Naehrlich, Rita Padoan, Deniz Dogru, Fiona Dunlevy, S. Fustik, Valérie Storms, Vladimir Bobrovnichy, Milan Rodić, Kęstutis Malakauskas, Meir Mei-Zahav, Marc Schlesser, Andreas Pfleger, Uros Krivec, Hana Kayserova, Oxana Turcu, María Dolores Pastor-Vivero, Guergana Petrova, Isabelle de Monestrol, and Elina Aleksejeva
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Surrogate endpoint, Incidence (epidemiology), medicine.medical_treatment, respiratory system, medicine.disease, Azithromycin, Cystic fibrosis, Cystic fibrosis, SARS-CoV-2, risk factors, observational, Covid-19, respiratory tract diseases, SDG 3 - Good Health and Well-being, Internal medicine, Oxygen therapy, Diabetes mellitus, Intensive care, Medicine, Lung transplantation, Original Research Article, business, medicine.drug
Abstract: BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes.MethodsIn this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis.ResultsUp to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0–18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7–35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4–17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function).ConclusionSARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s
Published: 2021
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9. TMEM16A/ANO1: Current Strategies and Novel Drug Approaches for Cystic Fibrosis

Author: Christie Mitri, Olivier Tabary, Harriet Corvol, Himanshu Sharma, 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), All India Institute of Medical Sciences [New Delhi], Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Mucoviscidose: physiopathologie et phénogénomique [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Gestionnaire, HAL Sorbonne Université 5, 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], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, QH301-705.5, Regulator, Cystic Fibrosis Transmembrane Conductance Regulator, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review, Gene mutation, Bioinformatics, Cystic fibrosis, Models, Biological, ANO1, cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Medicine, Animals, Humans, CFTR-independent therapy, Biology (General), [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, biology, business.industry, calcium-activated chloride channel, anoctamin-1, General Medicine, Potentiator, respiratory system, medicine.disease, 3. Good health, respiratory tract diseases, Hereditary Diseases, biology.protein, Chloride channel, business, Anoctamin-1, 030217 neurology & neurosurgery
Abstract: International audience; Cystic fibrosis (CF) is the most common of rare hereditary diseases in Caucasians, and it is estimated to affect 75,000 patients globally. CF is a complex disease due to the multiplicity of mutations found in the CF transmembrane conductance regulator (CFTR) gene causing the CFTR protein to become dysfunctional. Correctors and potentiators have demonstrated good clinical outcomes for patients with specific gene mutations; however, there are still patients for whom those treatments are not suitable and require alternative CFTR-independent strategies. Although CFTR is the main chloride channel in the lungs, others could, e.g., anoctamin-1 (ANO1 or TMEM16A), compensate for the deficiency of CFTR. This review summarizes the current knowledge on calcium-activated chloride channel (CaCC) ANO1 and presents ANO1 as an exciting target in CF.
Published: 2021
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10. Infant bronchiolitis dramatically reduced during the second French COVID‐19 outbreak

Author: Thibault Lecarpentier, Mathie Lorrot, Harriet Corvol, Romain Guedj, Ricardo Carbajal, and Pierre Louis Leger
Subjects: Male, Pediatrics, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Day care, Disease Outbreaks, 03 medical and health sciences, 0302 clinical medicine, Cost of Illness, 030225 pediatrics, Pandemic, medicine, Humans, Pediatrics, Perinatology, and Child Health, 030212 general & internal medicine, Covid‐19, business.industry, Brief Report, Infant, Newborn, COVID-19, Infant, Outbreak, General Medicine, medicine.disease, Bronchiolitis, Acute Bronchiolitis, Pediatrics, Perinatology and Child Health, Female, Regular Articles & Brief Reports, France, Seasons, Curfew, business, Healthcare system
Abstract: Acute bronchiolitis is one of the most common health burdens in infants worldwide and leads to frequent hospitalisation, morbidity and mortality (1). Children have been relatively spared by the COVID-19 pandemic, but reports of multisystem inflammatory syndrome (2) and probable long-term COVID (3) effects in children have started to emerge. One major concern was whether the overlap of the pandemic and seasonal bronchiolitis would put substantial pressure on healthcare systems. Bronchiolitis has a predictable seasonal pattern, primarily in autumn and winter, and in France this is between October and February. The second COVID-19 wave in France led to a two-week night curfew from 17 October 2020, followed by a full lockdown on 30 October. However, day care centres and primary and secondary schools remained open.
Published: 2021
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11. Severe Acute Respiratory Syndrome Coronavirus 2 Variant Delta Infects All 6 Siblings but Spares Comirnaty (BNT162b2, BioNTech/Pfizer)-Vaccinated Parents

Author: Nadia Nathan, Sidonie Lambert, Harriet Corvol, Aurélie Schnuriger, and Blandine Prevost
Subjects: Delta, Parents, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), evasion, resistance, Major Articles and Brief Reports, spike mutation, Immunology and Allergy, Medicine, Humans, neutralizing antibodies, BNT162 Vaccine, business.industry, SARS-CoV-2, infectivity, Siblings, COVID-19, Indian variant, Virology, fitness, Infectious Diseases, AcademicSubjects/MED00290, Covid-2019, antibody escape, business, B.1.617
Abstract: The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that 2 key mutations seen in the receptor-binding domain, L452R and E484Q, would have additive effects on evasion of neutralizing antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine-elicited neutralizing antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.
Published: 2021

12. Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020

Author: Halyna Makukh, Andrea Dugac Vukic, Meir Mei-Zahav, Tsitsino Parulava, Harriet Corvol, Godfrey Fletcher, Rita Padoan, S. Fustik, Silke van Koningsbruggen-Rietschel, Fiona Dunlevy, Andreas Jung, Hana Kayserova, Satenik Harutyunyan, Siobhán B. Carr, Domenique Zomer-van Ommen, Łukasz Woźniacki, Svetlana Keegan, Elena Kondratyeva, Jacqui G. van Rens, Elpis Hatziagorou, Carla Colombo, Pedro Mondejar-Lopez, Vincent Gulmans, Anita Senstad Wathne, María Dolores Pastor-Vivero, Milan Macek, Egil Bakkeheim, Milan Rodić, Sevgi Pekcan, Filia Diamantea, Elliott McClenaghan, Géraldine Daneau, Guergana Petrova, Kęstutis Malakauskas, Marko Krasnyk, Yasemin Gokdemir, Panayiotis K. Yiallouros, Elise Lammertyn, Marc Schlesser, Edward F. McKone, Andreas Pfleger, Olga I. Simonova, Luísa Pereira, Elena Zhekaite, Anders Lindblad, Oxana Turcu, Andrea Párniczky, Isabelle de Monestrol, Duška Tješić-Drinković, Elina Aleksejeva, Uro Krivecs, Lutz Naehrlich, Elena Amelina, A. Zolin, Pierre-Régis Burgel, Vladimir Bobrovnichy, Annalisa Orenti, Alena Bilkova, Deniz Dogru, Liviu Pop, Marco Salvatore, Nataliya Kashirskaya, Irena Kasmi, Keith G. Brownlee, Pavel Drevinek, Hanne Vebert Olesen, Rebecca Cosgriff, Lydie Lemonnier-Videau, A. Fox, Ivan Bambir, Naehrlich, Lutz, Orenti, Annalisa, Dunlevy, Fiona, Kasmi, Irena, Harutyunyan, Satenik, Pfleger, Andreas, Keegan, Svetlana, Daneau, Geraldine, Petrova, Guergana, Tjesic-Drinkovic, Duska, Yiallouros, Panayioti, Bilkova, Alena, Olesen, Hanne Vebert, Burgel, Pierre-Regis, Parulava, Tsitsino, Diamantea, Filia, Parniczky, Andrea, McKone, Edward F., Mei-Zahav, Meir, Salvatore, Marco, Colombo, Carla, Aleksejeva, Elina, Malakauskas, Kestutis, Schlesser, Marc, Fustik, Stojka, Turcu, Oxana, Zomer-van Ommen, Domenique, Wathne, Anita Senstad, Wozniacki, Lukasz, Pereira, Luisa, Pop, Liviu, Kashirskaya, Nataliya, Rodic, Milan, Kayserova, Hana, Krivecs, Uro, Mondejar-Lopez, Pedro, de Monsterol, Isabelle, Dogru, Deniz, Makukh, Halyn, Cosgriff, Rebecca, van Koningsbruggen-Rietschel, Silke, Jung, Andreas, Bobrovnichy, Vladimir, Bambir, Ivan, Vukic, Andrea Dugac, Drevinek, Pavel, Macek, Milan, Jr., Corvol, Harriet, Lemonnier-Videau, Lydie, Hatziagorou, Elpis, Fletcher, Godfrey, Padoan, Rita, Gulmans, Vincent, Bakkeheim, Egil, Kondratyeva, Elena, Amelina, Elena, Zhekaite, Elena, Simonova, Olga, Pastor-Vivero, Maria Dolores, Lindblad, Anders, Gokdemir, Yasemin, Pekcan, Sevgi, Brownlee, Keith, McClenaghan, Elliot, Carr, Siobhan, Lammertyn, Elise, Zolin, Anna, Fox, Alice, Krasnyk, Marko, and Van Rens, Jacqui
Subjects: 0301 basic medicine, Male, COVID-19/diagnosis, IMPACT, Epidemiology, Cystic fibrosis, 0302 clinical medicine, Cystic Fibrosis/complications, Case fatality rate, Medicine, Registries, Child, education.field_of_study, Incidence (epidemiology), Incidence, Middle Aged, Vaccination, Europe, Hospitalization, medicine.anatomical_structure, Child, Preschool, Female, Covid-19, Lung Transplantation, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Adolescent, Critical Care, Population, Article, Europe/epidemiology, 03 medical and health sciences, Young Adult, Intensive care, Internal medicine, Humans, education, Retrospective Studies, Lung, business.industry, SARS-CoV-2, Infant, Newborn, Infant, medicine.disease, cystic fibrosis, incidence, epidemiology, Transplantation, 030104 developmental biology, 030228 respiratory system, Pediatrics, Perinatology and Child Health, business
Abstract: Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/10 0 0 pwCF. Incidence was higher in lung-transplanted patients (n = 23) versus non transplanted patients (n = 107) (8.43 versus 2.36 cases/10 0 0). Incidence was higher in pwCF versus the age-matched general population in the age groups < 15, 15-24, and 25-49 years (p < 0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p = 0.133). Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
Published: 2021
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13. Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits

Author: Johanna M. Rommens, Pierre-Yves Boëlle, Scott M. Blackman, Hua Ling, Harriet Corvol, Lisa J. Strug, Loïc Guillot, Rhonda G. Pace, Garry R. Cutting, Briana Vecchio-Pagan, Michael R. Knowles, Mitch Drumm, Peng Zhang, Elizabeth W. Pugh, Karen S. Raraigh, and Melis A. Aksit
Subjects: Adult, Male, medicine.medical_specialty, endocrine system diseases, Adolescent, Cystic Fibrosis, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Cystic fibrosis-related diabetes, 030209 endocrinology & metabolism, Genome-wide association study, Type 2 diabetes, Bioinformatics, Biochemistry, Cohort Studies, Young Adult, 03 medical and health sciences, Diabetes mellitus genetics, Quantitative Trait, Heritable, 0302 clinical medicine, Endocrinology, Risk Factors, Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, Genetic Predisposition to Disease, Child, education, 030304 developmental biology, Clinical Research Article, 0303 health sciences, Type 1 diabetes, education.field_of_study, Genes, Modifier, business.industry, Biochemistry (medical), nutritional and metabolic diseases, medicine.disease, Diabetes Mellitus, Type 2, Female, France, business, TCF7L2, Genome-Wide Association Study
Abstract: Context Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants. Objective To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes. Design and Patients A genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for type 1 diabetes (T1D), T2D, and diabetes endophenotypes were tested for association with CFRD. Results Genome-wide significance was obtained for variants at a novel locus (PTMA) and 2 known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, postchallenge glucose concentration, and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprising variants selected from these PRSs (with a false discovery rate < 0.1) and the genome-wide significant variants was associated with CFRD in a replication population. Conclusions CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population.
Published: 2019
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14. SLC6A14 Modulates Lung Disease Severity in Cystic Fibrosis and Affects mTOR Phosphorylation and Bronchial Epithelial Repair

Author: Erika N. Sutanto, Fatiha Merabtene, Pierre-Yves Boëlle, Elisabeth Longchampt, Julia Mercier, Loïc Guillot, Edouard Sage, Manon Ruffin, Julie Mésinèle, Anthony Kicic, Claire Calmel, and Harriet Corvol
Subjects: Text mining, business.industry, Lung disease, Cancer research, medicine, Phosphorylation, respiratory system, medicine.disease, business, Cystic fibrosis, PI3K/AKT/mTOR pathway
Abstract: Cystic fibrosis (CF), due to variants in CFTR gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 promoter activity and the role of SLC6A14 in mammalian target of rapamycin (mTOR) signaling pathway and airway epithelial repair. We confirm that SLC6A14 SNP rs3788766 is associated with lung disease severity in pwCF (p=0.020; n=3,257, pancreatic insufficient, aged 6 to 40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation and bronchial epithelial repair rates in wound healing assays. In conclusion, SLC6A14 rs3788766 G allele is associated with lower lung function in pwCF. SLC6A14, whose transcriptional promoter activity varies according to rs3788766 genotype, is involved in mTOR signaling and bronchial epithelial repair. This study suggests that SLC6A14 might influence CF lung phenotype via mTOR and epithelial repair mechanisms modulation.
Published: 2021
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15. Achromobacter xylosoxidans airway infection is associated with lung disease severity in children with cystic fibrosis

Author: Harriet Corvol, Laura Berdah, Charlotte Marsac, Isabelle Sermet-Gaudelus, Guillaume Thouvenin, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Pneumologie pédiatrique [CHU Trousseau], 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Mucoviscidose: physiopathologie et phénogénomique [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), and Gestionnaire, Hal Sorbonne Université
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Cystic Fibrosis, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Cystic fibrosis, 03 medical and health sciences, Emerging pathogen, 0302 clinical medicine, Internal medicine, Genotype, medicine, 030212 general & internal medicine, biology, business.industry, Retrospective cohort study, Achromobacter xylosoxidans, Original Articles, biology.organism_classification, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030228 respiratory system, Lung disease, Medicine, Airway, business
Abstract: Background Despite the increasing prevalence of Achromobacter xylosoxidans lung infection in patients with cystic fibrosis (CF), its clinical pathogenicity remains controversial. The objective of this study was to evaluate the effects of this emerging bacterium on lung disease severity in CF children. Methods This case–control retrospective study took place in two French paediatric CF centres. 45 cases infected by A. xylosoxidans were matched for age, sex, CFTR genotypes and pancreatic status to 45 never-infected controls. Clinical data were retrieved from clinical records over the 2 years before and after A. xylosoxidans initial infection. Results At infection onset, lung function was lower in cases compared with controls (p=0.006). Over the 2 years prior to A. xylosoxidans acquisition, compared with controls, cases had more frequent pulmonary exacerbations (p=0.02), hospitalisations (p=0.05), and intravenous (p=0.03) and oral (p=0.001) antibiotic courses. In the 2 years following A. xylosoxidans infection, cases remained more severe with more frequent pulmonary exacerbations (p=0.0001), hospitalisations (p=0.0001), and intravenous (p=0.0001) and oral antibiotic courses (p=0.0001). Lung function decline tended to be faster in cases (−5.5% per year) compared with controls (−0.5% per year). Conclusions This case–control study demonstrates that A. xylosoxidans occurs more frequently in the patients with the worse lung disease. Further studies assessing the pathogenicity of this emerging pathogen and international treatment recommendations are warranted., The prevalence of the opportunistic pathogen Achromobacter xylosoxidans increases in patients with CF. This study shows an association between airway infection with this bacterium and more severe lung disease in children with CF. https://bit.ly/3a7ioSi
Published: 2021
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16. Benefits and risks of bronchoalveolar lavage in severe asthma in children

Author: Blandine Prevost, Nadia Nathan, Laura Berdah, Raja Ben Tkhayat, Harriet Corvol, Jocelyne Just, Jessica Taytard, Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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], Service d'Allergologie pédiatrique [CHU Trousseau], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], and Gestionnaire, Hal Sorbonne Université
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Severe asthma, Asthma management, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, Bronchoscopy, Internal medicine, Original Research Articles, Medicine, 030212 general & internal medicine, Flexible bronchoscopy, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine.diagnostic_test, business.industry, Asthma symptoms, respiratory system, University hospital, Asthma, 3. Good health, respiratory tract diseases, Bronchoalveolar lavage, 030228 respiratory system, business, Tracheobronchial malacia
Abstract: Background Although bronchoscopy can be part of the exploration of severe asthma in children, the benefit of bronchoalveolar lavage (BAL) is unknown. The present study aimed to decipher whether systematic BAL during a flexible bronchoscopy procedure could better specify the characteristics of severe asthma and improve asthma management. Material and methods The study took place in two departments of a university hospital in Paris. Children who underwent flexible bronchoscopy for the exploration of severe asthma between April 2017 and September 2019 were retrospectively included. Results In total, 203 children were included, among whom 107 had a BAL. BAL cell count was normal in most cases, with an increasing number of eosinophils with age, independently from the atopic status of the patients. Compared with bronchial aspiration only, BAL increased the rate of identified bacterial infection by 1.5. Nonatopic patients had more bacterial infections (p, Bronchoalveolar lavage can help characterise severe asthma in children. However, it can be poorly tolerated and, in most cases, its impact on the patient's management remains limited. https://bit.ly/39XOlMt
Published: 2021
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17. Correction to: Cystic fibrosis–related diabetes onset can be predicted using biomarkers measured at birth

Author: Julie Avolio, Lorna Kosteniuk, Mays Merjaneh, Emmanuelle Brochiero, Pearce G. Wilcox, Yu-Chung Lin, Nancy Morrison, Katherine Keenan, Mark A. Chilvers, April Price, Melinda Solomon, Damien Adam, Dimas Mateos-Corral, Felix Ratjen, Jennifer Pike, Bradley S. Quon, Scott M. Blackman, Vanessa McMahon, Anne L. Stephenson, Joe Reisman, Terry Viczko, Mary Jackson, Natalie Henderson, Naim Panjwani, Nathalie Vadeboncoeur, Émilie Maille, Caroline Burgess, Katie Griffin, Harriet Corvol, Danny Veniott, Lori Fairservice, Shaikh Iqbal, Angela Hillaby, Raquel Consunji-Araneta, Christine Donnelly, Guillaume Côté-Maurais, Emma Karlsen, Clare Smith, Elizabeth Tullis, Andrea Dale, Winnie Leung, Paula Barrett, Lei Sun, Mary Jane Smith, Daniel Hughes, Stéphanie Bégin, Janna Brusky, Candice Bjornson, Lynda Lazosky, Richard van Wylick, Michael D. Parkins, Yves Berthiaume, Lara Bilodeau, Johanna M. Rommens, Lisa J. Strug, Jennifer Itterman, Valerie Levesque, Fan Lin, Jiafen Gong, and Garry R. Cutting
Subjects: Canada, medicine.medical_specialty, Cystic Fibrosis, business.industry, Cystic fibrosis-related diabetes, Infant, Newborn, Medical laboratory, Correction, Cystic Fibrosis Transmembrane Conductance Regulator, medicine.disease, Gastroenterology, Human genetics, Internal medicine, Diabetes Mellitus, Humans, Medicine, business, Biomarkers, Genetics (clinical), Genome-Wide Association Study
Abstract: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes.Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies.The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies.We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.
Published: 2021
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18. Pulmonary Hemorrhage Revealing Multiple Vascular Malformations in a Child with KCNT1 Developmental Epileptic Encephalopathy

Author: Bénédicte Héron, Julie Cassibba, Harriet Corvol, Philippe Brenot, Diane Doummar, Hubert Ducou Le Pointe, Lauren Bitton, and Cyril Mignot
Subjects: Hemoptysis, Pathology, medicine.medical_specialty, Epilepsy, Vascular Malformations, business.industry, Epileptic encephalopathy, Vascular malformation, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, medicine.disease, Embolization, Therapeutic, Child, Preschool, Pediatrics, Perinatology and Child Health, medicine, Humans, Female, Pulmonary hemorrhage, business
Published: 2021
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19. 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
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20. COVID-19 vaccine prioritisation for people with cystic fibrosis

Author: Satenik Harutyunyan, Marco Salvatore, Rasa Ruseckaite, Elena Zhekayte, Keith G. Brownlee, Albert Faro, Luiz Vicente Ribeiro Ferreira da Silva Filho, Catherine A. Byrnes, Samar Rizvi, Siobhán B. Carr, Elena Kondratyeva, Andeas Jung, Harriet Corvol, Pierre Régis Burgel, Pedro Mondejar-Lopez, Bruce C. Marshall, Olzhas Abdrakhmanov, Géraldine Daneau, Peter G. Middleton, Susannah Ahern, Nataliya Kashirskaya, Lutz Nährlich, Alexander Elbert, Marco Zampoli, Vincent Gulmans, Elliot McClenaghan, Isabelle de Monestrol, M. Dolores Pastor-Vivero, R. Padoan, Hector Gutierrez, Joel Melo, Carla Colombo, Stephanie Y. Cheng, Christopher H. Goss, Anne L. Stephenson, Elena Amelina, Edward McKone, and Rebecca Cosgriff
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Cystic Fibrosis, business.industry, Health Priorities, Health Policy, Patient Selection, COVID-19, medicine.disease, Cystic fibrosis, Coronavirus, Pediatrics, Perinatology and Child Health, medicine, Humans, Intensive care medicine, business, Letter to the Editor, Vaccine, COVID
Published: 2021

21. Atypical Severe Organizing Pneumonia Following Coronavirus Disease 2019 in an Immunocompromised Teenager

Author: Harriet Corvol, Hubert Ducou Le Pointe, Blandine Prevost, Marie-Dominique Tabone, Jérôme Rambaud, Aurelia Alimi, and Aurélie Schnuriger
Subjects: Microbiology (medical), medicine.medical_specialty, ARDS, 2019-20 coronavirus outbreak, Adolescent, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Pneumonia, medicine.disease, Immunocompromised Host, Infectious Diseases, Pneumonia, Mycoplasma, medicine, Humans, Organizing pneumonia, Intensive care medicine, business
Published: 2021
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22. Lung ultrasound in children with interstitial lung disease: a pilot study

Author: Nadia Nathan, Laura Berdah, Fouad Madhi, Annick Clement, Houmam El Jurdi, Céline Delestrain, Harriet Corvol, Ralph Epaud, Nicolas Richard, and Guillaume Thouvenin
Subjects: medicine.medical_specialty, medicine.diagnostic_test, Adult patients, business.industry, Bilateral pleural effusion, Interstitial lung disease, Computed tomography, respiratory system, medicine.disease, respiratory tract diseases, Lung ultrasound, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Medicine, 030212 general & internal medicine, Radiology, business, Pleural line
Abstract: Introduction: Diagnosis and monitoring of interstitial lung disease (ILD) in children are mainly based on chest computed tomography (CT), resulting in significant exposure to x-rays. In adult patients, studies have shown a good sensitivity of the lung ultrasound (LUS) for detecting interstitial lesions, with a high correlation between LUS and CT images. The aim of this pilot study was to assess in children with ILD: (i) the feasibility of lung ultrasound and (ii) the comparability of LUS and CT images. Methods: LUS was performed in 5 children followed in the RespiRare® centre for an ILD of various aetiologies. Images visualized by LUS were described and compared to those seen at the latest chest CT. Results: The 5 children were 1.5, 2.5, 7, 11 and 16 years old respectively. Interstitial lesions were visualized by LUS in 4 of the 5 children, characterized by the presence of more than 3 confluent or spaced B lines per field, associated with an irregularity of the pleural line. Two children presented sub-pleural consolidations that were also seen on their CT. Bilateral pleural effusion was observed by LUS in one child. Only one child had a normal LUS while his CT showed some scattered micro-nodular lesions. Conclusion: This pilot study demonstrated a good correlation between LUS and CT images. As in adult patients, LUS could be an interesting tool for screening and monitoring children with ILD, reducing their exposure to x-rays in comparison to CT.
Published: 2020
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23. The Wide Spectrum of COVID-19 Clinical Presentation in Children

Author: Julien Jegard, Aurélie Schnuriger, Guillaume Aubertin, Chiara Sileo, Thibault Lecarpentier, Harriet Corvol, Guillaume Thouvenin, Nicolas Richard, Jessica Taytard, Nadia Nathan, Blandine Prevost, Laura Berdah, Isabelle Guellec, Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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], Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Gestionnaire, Hal Sorbonne Université, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], 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), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Mucoviscidose: physiopathologie et phénogénomique [CRSA], and 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)
Subjects: Pediatrics, medicine.medical_specialty, Abdominal pain, [SDV]Life Sciences [q-bio], lcsh:Medicine, Context (language use), MIS-C, Disease, 030204 cardiovascular system & hematology, Overweight, Article, 03 medical and health sciences, 0302 clinical medicine, children, Medicine, 030212 general & internal medicine, business.industry, SARS-CoV-2, infants, lcsh:R, COVID-19, General Medicine, acute respiratory distress syndrome, medicine.disease, Obesity, Acute chest syndrome, 3. Good health, [SDV] Life Sciences [q-bio], Cohort, Presentation (obstetrics), medicine.symptom, business, PIMS-TS
Abstract: Background: Ten months after its appearance in December 2019, SARS-CoV-2 has infected more than 25 million patients worldwide. Because children were first identified as potential spreaders of the virus, schools were closed in several countries. However, it rapidly became evident that the number of hospitalized children infected by SARS-CoV-2 was dramatically lower than that of adults. To date, only hypotheses have been raised to explain this difference, so it is of great importance to describe the presentation of this disease among children. Here, we describe a wide spectrum of COVID-19 manifestation in children in a dedicated pediatric unit in France. Methods: Patients hospitalized with COVID-19 who were diagnosed on the basis of either positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs and/or typical aspects in chest-computed tomography (CT) were included between March and May 2020 in Paris. Results: Twenty-three patients were included on the basis of positive RT-PCR (n = 20) and/or typical aspects in CT (n = 4). The median age was 4.9 years [0.1&ndash, 17.6]. Patients were grouped by age (&lt, 2 years old: n = 14, 61%, 2&ndash, 10 years old: n = 2, 9%, &gt, 10 years old: n = 7, 30%). Overweight or obesity was reported in only three patients. At presentation, the most frequent symptom in the overall cohort was fever (n = 18, 78%), followed by acute rhinitis (n = 9, 64%) and cough (n = 7, 50%) in the under 2-year-old group and cough (n = 4, 57%), fatigue, dyspnea and abdominal pain (n = 3, 43% each) in the over 10-year-old group. Five patients required ICU treatment, four of whom were aged &gt, 10 years, two presented with acute myocarditis, and two were sickle cell disease patients who presented with acute chest syndrome. Discussion and conclusion: The youngest patients seem to present milder forms of COVID-19 without the need for ICU treatment and with a shorter length of hospitalization. More severe evolutions were observed in teenagers, with, however, favorable outcomes. Given the context of closed schools and confinement, the infection of these children suggests intra-familial transmission that needs to be further assessed. This description might help to understand the intriguing differences in COVID-19 severity across age-classes.
Published: 2020
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24. 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
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25. Dramatic improvement after tocilizumab of severe COVID ‐19 in a child with sickle cell disease and acute chest syndrome

Author: Marie-Hélène Odièvre, Nadia Nathan, Hubert Ducou Le Pointe, Jenny Youn, Slimane Allali, Jessica Taytard, Anne Sophie Romain, Charles de Marcellus, and Harriet Corvol
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), biology, business.industry, Cell, Disease, Hematology, medicine.disease, biology.organism_classification, Virology, Acute chest syndrome, chemistry.chemical_compound, medicine.anatomical_structure, Tocilizumab, chemistry, Pandemic, medicine, business, Betacoronavirus
Published: 2020
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26. Atypical presentation of COVID-19 in young infants

Author: Nadia Nathan, Blandine Prevost, and Harriet Corvol
Subjects: 2019-20 coronavirus outbreak, biology, Coronavirus disease 2019 (COVID-19), business.industry, General Medicine, biology.organism_classification, medicine.disease, medicine.disease_cause, Virology, Young infants, Pneumonia, Pandemic, Medicine, Presentation (obstetrics), business, Betacoronavirus, Coronavirus
Published: 2020
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27. Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity

Author: Harriet Corvol, Manon Ruffin, Alekh Paranjapye, Ann Harris, Case Western Reserve University [Cleveland], 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], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Locus (genetics), Cystic fibrosis, Severity of Illness Index, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Medicine, Humans, Gene, Transcription factor, Genetic Association Studies, Genetics, Genes, Modifier, business.industry, Genetic heterogeneity, Genetic Variation, respiratory system, medicine.disease, Phenotype, digestive system diseases, Chromatin, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, Pediatrics, Perinatology and Child Health, business
Abstract: In patients with cystic fibrosis (CF), genetic variants within and outside the CFTR locus contribute to the variability of the disease severity. CFTR transcription is tightly regulated by cis-regulatory elements (CREs) that control the three-dimensional structure of the locus, chromatin accessibility and transcription factor recruitment. Variants within these CREs may contribute to the pathophysiology and to the phenotypic heterogeneity by altering CFTR transcript abundance. In addition to the CREs, variants outside the CFTR locus, namely "modifiers genes", may also be associated with the clinical variability. This review addresses variants at the CFTR locus itself and CFTR CREs, together with the outcomes of the latest modifier gene studies with respect to the different CF phenotypes.
Published: 2020
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28. Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients

Author: Dominique Debray, Loïc Guillot, Harriet Corvol, Annick Clement, Pierre-Yves Boëlle, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-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), 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), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), French CF Modifier Gene Study Investigators, BOELLE, Pierre-Yves, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), Mucoviscidose: physiopathologie et phénogénomique [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), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Service de Pneumologie pédiatrique [CHU Trousseau], and CHU Trousseau [APHP]
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Meconium Ileus, Cystic fibrosis, Young Adult, 03 medical and health sciences, Liver disease, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, Risk Factors, medicine, Humans, Young adult, Child, Adverse effect, Retrospective Studies, 2. Zero hunger, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Hepatology, business.industry, cirrhosis, Incidence, Liver Diseases, Incidence (epidemiology), Ursodeoxycholic Acid, portal hypertension, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Ursodeoxycholic acid, 3. Good health, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, meconium ileus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, 030211 gastroenterology & hepatology, France, liver disease, business, medicine.drug
Abstract: International audience; Cystic fibrosis (CF)-related liver disease (CFLD) is a common symptom in patients with CF. However, its prevalence, risk factors, and evolution are unclear. We analyzed a large database of patients with CF to investigate the incidence of CFLD, its related risk factors, and the use and effect of ursodeoxycholic acid (UDCA) treatment. We retrospectively analyzed 3,328 CF patients with pancreatic insufficiency born after 1985 and recruited into the French CF Modifier Gene Study since 2004. We determined liver status, age at CFLD and severe CFLD onset, sex, CFTR genotype, history of meconium ileus, treatment with UDCA, and respiratory and nutritional status. The incidence of CFLD increased by approximately 1% every year, reaching 32.2% by age 25. The incidence of severe CFLD increased only after the age of 5, reaching 10% by age 30. Risk factors for CFLD and severe CFLD were male sex, CFTR F508del homozygosity, and history of meconium ileus. Increasingly precocious initiation of UDCA treatment did not change the incidence of severe CFLD. Finally, patients with severe CFLD had worse lung function and nutritional status than other CF patients. Conclusion: CFLD occurs not only during childhood but also later in the lifetime of patients with CF; male sex, CFTR F508del homozygosity, and history of meconium ileus are independent risk factors for CFLD development; earlier use of UDCA over the last 20 years has not changed the incidence of severe CFLD, leading to questions about the use of this treatment in young children given its possible adverse effects.
Published: 2018
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29. 644: Genetic variants that modify severity of CF lung disease: Update from the CF genome project

Author: Hua Ling, Hong Dang, F. Wright, Wanda K. O'Neal, Rhonda G. Pace, Ronald L. Gibson, Yi-Hui Zhou, Scott M. Blackman, Lisa J. Strug, Y. Li, Michael J. Bamshad, Harriet Corvol, Garry R. Cutting, Michael R. Knowles, and P. Gallins
Subjects: Pulmonary and Respiratory Medicine, Genetics, Lung disease, business.industry, Pediatrics, Perinatology and Child Health, Genetic variants, medicine, Genome project, medicine.disease, business, Cystic fibrosis
Published: 2021
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30. 642: SLC6A14 is associated with lung function in patients with cystic fibrosis, regulates epithelial repair and mTOR signaling in bronchial epithelial cells

Author: Manon Ruffin, Anthony Kicic, Erika N. Sutanto, Julie Mésinèle, Claire Calmel, Julia Mercier, Pierre-Yves Boëlle, Loïc Guillot, and Harriet Corvol
Subjects: Pulmonary and Respiratory Medicine, Mtor signaling, business.industry, Pediatrics, Perinatology and Child Health, Cancer research, medicine, In patient, medicine.disease, business, Cystic fibrosis, Lung function
Published: 2021
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31. 410: Pseudomonas aeruginosa modulates SARS-CoV-2 infectivity in CF airway epithelial cells by increasing expression of the host protease TMPRSS2

Author: Andrés Pizzorno, Jeanne Bigot, O. Terrier, M. Rosa-Calatrava, Claire Calmel, Viviane Balloy, Julia Mercier, Manon Ruffin, Loïc Guillot, and Harriet Corvol
Subjects: Pulmonary and Respiratory Medicine, Infectivity, Protease, Pseudomonas aeruginosa, business.industry, Host (biology), Posters, medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Infection/Microbiology, medicine.disease_cause, medicine.disease, TMPRSS2, Cystic fibrosis, Microbiology, Pediatrics, Perinatology and Child Health, medicine, Airway, business
Published: 2021

32. Respiratory Epithelial Cells Can Remember Infection: A Proof of Concept Study

Author: Viviane Balloy, Manon Ruffin, Harriet Corvol, Juliette Guitard, Michel Chignard, Jeanne Bigot, Christophe Hennequin, and Loïc Guillot
Subjects: Lipopolysaccharides, 0301 basic medicine, Lipopolysaccharide, Inflammation, Respiratory Mucosa, medicine.disease_cause, Proof of Concept Study, Epigenesis, Genetic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Humans, Immunology and Allergy, Medicine, RNA, Messenger, 030212 general & internal medicine, Epigenetics, Innate immune system, biology, Respiratory tract infections, business.industry, Pseudomonas aeruginosa, Epithelial Cells, Toll-Like Receptor 4, 030104 developmental biology, Infectious Diseases, Gene Expression Regulation, chemistry, Immunology, biology.protein, medicine.symptom, business, Immunologic Memory, Homeostasis, Flagellin
Abstract: Human bronchial epithelial cells play a key role in airway immune homeostasis. We hypothesized that these sentinel cells can remember a previous contact with pathogen compounds and respond nonspecifically to reinfection, a phenomenon called innate immune memory. We demonstrated that their pre-exposure to Pseudomonas aeruginosa flagellin modify their inflammatory response to a second, non-related stimulus, including live pathogens or lipopolysaccharide. Using histone acetyltransferase and methyltransferase inhibitors, we showed that this phenomenon relied on epigenetic regulation. This report is a major breakthrough in the field of multi-microbial respiratory tract infections, wherein control of inflammatory exacerbations is a major therapeutic issue.
Published: 2019
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33. 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
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34. AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations

Author: Garry R. Cutting, David E. Nethery, Mitchell L. Drumm, Eric Barbato, Neha Joshi, Paul Litman, Cara Campanaro, Abdus Sattar, Rebecca J. Darrah, Michael R. Knowles, Frank J. Jacono, Lisa J. Strug, Craig A. Hodges, Anna L. Mitchell, Harriet Corvol, Jennifer Frey, Gestionnaire, Hal Sorbonne Université, Case Western Reserve University [Cleveland], Department of Medicine [Cleveland, OH, USA], Veterans Affairs Medical Center, 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), Sorbonne Université (SU), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Johns Hopkins University School of Medicine [Baltimore], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), The Hospital for sick children [Toronto] (SickKids), This work was supported by Cystic Fibrosis Foundation grants DARRAH17PO and DARRAH1610 (to RJD), as well as DRUMM15RO and DRUMM15R1 (to MLD), Gilead Sciences Research Scholars Program in Cystic Fibrosis award (to RJD), as well as VA Research Service BLR&D Merit Review Award I01BX000873 (to FJJ). 1R56HL136293-01 (to RJD) from NIH/NHLBI., Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]
Subjects: Lung Diseases, Male, 0301 basic medicine, Angiotensin signaling, Cystic Fibrosis, Pyridines, GWAS follow up, DNA Mutational Analysis, Genome-wide association study, Angiotensin II Type 2 Receptor Blockers, Gene mutation, Cystic fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Pulmonary function testing, Mice, 0302 clinical medicine, Medicine, Child, Lung, Mice, Knockout, Imidazoles, Forced Expiratory Flow Rates, 3. Good health, Female, Pulmonary and Respiratory Medicine, Subset Analysis, Pulmonary function, Genotype, Locus (genetics), Receptor, Angiotensin, Type 2, Article, 03 medical and health sciences, Animals, Humans, Retrospective Studies, business.industry, DNA, medicine.disease, Mouse models of airway disease, Disease Models, Animal, 030104 developmental biology, 030228 respiratory system, Mutation, Pediatrics, Perinatology and Child Health, Immunology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Type-2 Angiotensin II Receptor, business, Antagonism, Follow-Up Studies
Abstract: International audience; BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF.METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning.RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels.CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.
Published: 2019
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35. SERPINA1 Z allele is associated with cystic fibrosis liver disease

Author: Harriet Corvol, Dominique Debray, Pierre-Yves Boëlle, Loïc Guillot, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), 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), CHU Necker - Enfants Malades [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), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Guillot, Loic, Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), 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), and BOELLE, Pierre-Yves
Subjects: Male, Cirrhosis, Cystic Fibrosis, Severity of Illness Index, Cystic fibrosis, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Liver disease, 0302 clinical medicine, Esophageal varices, Risk Factors, Medicine, Cumulative incidence, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Liver Diseases, Incidence (epidemiology), Hazard ratio, 3. Good health, Liver, Child, Preschool, Female, Adult, medicine.medical_specialty, Adolescent, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Young Adult, 03 medical and health sciences, Internal medicine, Hypertension, Portal, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetic Association Studies, 030304 developmental biology, business.industry, Infant, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, alpha 1-Antitrypsin, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: International audience; Purpose: The SERPINA1 Z allele is associated with cystic fibrosis (CF)-related liver disease (CFLD), a common manifestation in patients with CF. We estimated CFLD incidence based on the SERPINA1 genotype in 3328 CF patients with CFLD-phenotype information.Methods: The associations of SERPINA1 Z (rs28929474) and S (rs17580) alleles with age at CFLD onset and the development of CFLD-related complications (severe liver disease with cirrhosis, portal hypertension, esophageal varices) were analyzed.Results: Overall, 3% of patients carried the SERPINA1 Z allele and 13% carried the S allele. The cumulative incidence of CFLD increased more rapidly in patients carrying the Z allele (hazard ratio [HR] = 1.6; 95% confidence interval [CI] = 1.1–2.4, P = 0.019), reaching 47% by age 25 compared with 30% in noncarriers. Increased risk was similar for patients with severe CFLD (HR = 1.5, 95% CI = 0.7–3.2, P = 0.31) but failed to reach significance due to a limited sample size of Z-allele carriers. No significant effect was found for the S allele.Conclusion: CF patients carrying the SERPINA1 Z allele had an increased risk of developing CFLD and related complications compared with noncarriers. Routine SERPINA1 Z genotyping upon CF diagnosis is warranted for identifying patients worthy of closer liver disease monitoring.
Published: 2019
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36. Modifier Genes in Cystic Fibrosis-related Liver Disease

Author: Chantal Housset, Dominique Debray, Harriet Corvol, CHU Necker - Enfants Malades [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), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Liver Cirrhosis, Genotype, Context (language use), Bioinformatics, Cystic fibrosis, cystic fibrosis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Fibrosis, medicine, Animals, Humans, Allele, innate immunity, Alleles, Innate immune system, Serpina1, biology, business.industry, Gastroenterology, cholangiopathy, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Pathophysiology, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, alpha 1-Antitrypsin, biology.protein, 030211 gastroenterology & hepatology, business
Abstract: International audience; PURPOSE OF REVIEW: Cystic fibrosis (CF; OMIM 219700) is caused by variations in the cystic fibrosis transmembrane conductance regulator gene. CF-related liver disease (CFLD) affects approximately one-third of patients with CF, but the severity of CFLD is highly variable. This review provides the latest knowledge in the pathophysiology and CF genetic modifier research in CFLD.RECENT FINDINGS: So far, the only modifier gene validated in CFLD is SERPINA1 (α-1-antitrypsin) Z allele. Recent studies support the view that cholangiopathy arising in CF is the result of an ill-adapted innate immune response to endotoxins coming from the intestine and triggering a pro-inflammatory response.SUMMARY: The pathophysiology of liver disease remains uncertain and so far, no therapy has proven effective to prevent the progression of CFLD. A better understanding of the pathophysiology and the effect of environmental and non-cystic fibrosis transmembrane conductance regulator genetic influences in the context of CFLD development would help improve management and develop new drug therapies.
Published: 2019
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37. P083 Clinical progression of SARS-CoV-2 infection in people with cystic fibrosis: a global observational study

Author: R. Padoan, Bruce C. Marshall, Satenik Harutyunyan, Pierre-Régis Burgel, Keith G. Brownlee, O. Abdrakhmanov, Christopher H. Goss, Stephanie Y. Cheng, Edward F. McKone, Alexander Elbert, Cass Byrnes, María Dolores Pastor-Vivero, I. de Monestrol, Peter G. Middleton, Rebecca Cosgriff, Siobhán B. Carr, Géraldine Daneau, Rasa Ruseckaite, L. Nährlich, Andreas Jung, Harriet Corvol, Susannah Ahern, Marco Zampoli, Marco Salvatore, Nataliya Kashirskaya, Anne L. Stephenson, Elliot McClenaghan, Albert Faro, Pedro Mondejar-Lopez, Hector H. Gutierrez, Joel Melo, L. V. R. da Silva Filho, Vincent Gulmans, Samar Rizvi, and Claudio Colombo
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Descriptive statistics, Posters, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Logistic regression, medicine.disease, Cystic fibrosis, Pediatrics, Perinatology and Child Health, Pandemic, medicine, Observational study, Intensive care medicine, business, Epidemiology/Registry, Clinical progression
Abstract: Objectives: As the novel coronavirus (SARS-CoV-2) pandemic continues, people with cystic fibrosis (CF) have been identified as being a vulnerable group. It is essential that people with CF, their families and their clinical teams have the most up-to-date information on the impact of SARS-CoV-2 on their health. This study aims to characterise the impact of SARS-CoV-2 infection in people with CF throughout 2020, identify factors that predict clinical progression of COVID-19, and to describe medium-term follow-up of people who have been infected. Methods: The ‘Cystic Fibrosis Registry Global Harmonization Group’ is a worldwide network of CF Registries that each contributed data on people with CF diagnosed with SARS-CoV-2 infection. In this analysis, we will report on cases contributed from 22 countries diagnosed between 1st February and 13th December 2020. We will present demographic, pre-infection clinical characteristics, symptoms, infection management and outcomes. We will use multivariable logistic regression to assess predictors for hospitalisation with respiratory support and intensive care admission as the outcomes of interest representing clinical progression of COVID-19. Descriptive analysis of medium-term follow-up BMI and FEV1% predicted values will also be undertaken. Results: Results pending. Expected cohort size >1,000, including the 181 previously reported in our paper “The global impact of SARS-CoV-2 in 181 people with cystic fibrosis.” Conclusion: It is expected that the findings of this study will have important implications for shielding advice, clinical care and vaccine prioritisation for people with CF.
Published: 2021
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38. Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis

Author: Garry R. Cutting, Joseph M. Collaco, Karen S. Raraigh, Michael R. Knowles, Johanna M. Rommens, Patrick R. Sosnay, Pierre-Yves Boëlle, Lisa J. Strug, Rhonda G. Pace, John McGready, Scott M. Blackman, and Harriet Corvol
Subjects: Adult, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pathology, Cystic Fibrosis, Population, Sweat chloride, Cystic Fibrosis Transmembrane Conductance Regulator, Critical Care and Intensive Care Medicine, Cystic fibrosis, Ivacaftor, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chlorides, Internal medicine, Genotype, medicine, Humans, Sweat, education, education.field_of_study, integumentary system, biology, business.industry, Lumacaftor, respiratory system, Potentiator, medicine.disease, digestive system diseases, Cystic fibrosis transmembrane conductance regulator, respiratory tract diseases, 030104 developmental biology, Endocrinology, 030228 respiratory system, chemistry, biology.protein, Female, business, Biomarkers, medicine.drug
Abstract: Expanding the use of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors for the treatment of cystic fibrosis (CF) requires precise and accurate biomarkers. Sweat chloride concentration provides an in vivo assessment of CFTR function, but it is unknown the degree to which CFTR mutations account for sweat chloride variation.To estimate potential sources of variation for sweat chloride measurements, including demographic factors, testing variability, recording biases, and CFTR genotype itself.A total of 2,639 sweat chloride measurements were obtained in 1,761 twins/siblings from the CF Twin-Sibling Study, French CF Modifier Gene Study, and Canadian Consortium for Genetic Studies. Variance component estimation was performed by nested mixed modeling.Across the tested CF population as a whole, CFTR gene mutations were found to be the primary determinant of sweat chloride variability (56.1% of variation) with contributions from variation over time (e.g., factors related to testing on different days; 13.8%), environmental factors (e.g., climate, family diet; 13.5%), other residual factors (e.g., test variability; 9.9%), and unique individual factors (e.g., modifier genes, unique exposures; 6.8%) (likelihood ratio test, P 0.001). Twin analysis suggested that modifier genes did not play a significant role because the heritability estimate was negligible (HVariation in the CFTR gene is the predominant cause of sweat chloride variation; most of the non-CFTR variation is caused by testing variability and unique environmental factors. If test precision and accuracy can be improved, sweat chloride measurement could be a valuable biomarker for assessing response to therapies directed at mutant CFTR.
Published: 2016
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39. Nouvelles thérapeutiques de la mucoviscidose ciblant le gène ou la protéine CFTR

Author: Christophe Marguet, M. Murris-Espin, Anne Munck, Dominique Hubert, V. Colomb-Jung, Harriet Corvol, and Stéphanie Bui
Subjects: Pulmonary and Respiratory Medicine, Gynecology, medicine.medical_specialty, biology, business.industry, Genetic therapy, Cystic fibrosis transmembrane conductance regulator, Ivacaftor, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, medicine, biology.protein, 030212 general & internal medicine, business, medicine.drug
Abstract: Resume Introduction Le traitement de la mucoviscidose est reste longtemps symptomatique. Des therapeutiques ciblant la proteine CFTR defectueuse commencent a etre disponibles. Etat des connaissances Les resultats de la therapie genique restent modestes mais une etude clinique recente montre un benefice sur le VEMS. Les avancees concernent surtout les therapies ciblant la proteine CFTR. Une amelioration respiratoire importante (gain de VEMS d’environ 10 % et baisse des exacerbations respiratoires) a ete obtenue sous ivacaftor, potentiateur de CFTR, chez les patients porteurs de mutations gating, aboutissant a l’obtention d’une Autorisation de mise sur le marche (en 2012 pour la mutation G551D et en 2015 pour des mutations plus rares). Chez les patients homozygotes phe508del, l’association de l’ivacaftor a un correcteur de CFTR (lumacaftor) permet une amelioration respiratoire plus modeste. L’efficacite de l’ataluren chez des patients porteurs de mutations non-sens est en cours d’evaluation. Perspectives De nouveaux correcteurs et potentiateurs de CFTR sont en developpement. Ils pourraient changer le cours de la maladie mais les enjeux medicoeconomiques ne doivent pas etre sous-estimes. Conclusion L’ivacaftor peut etre prescrit chez les patients porteurs d’une mutation de classe 3 a partir de l’âge de 6 ans. Prochainement, l’Orkambi® sera disponible pour les patients homozygotes phe508del a partir de 12 ans.
Published: 2016
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40. Ultrasonography and Computed Tomographic Manifestations of Abdominal Sarcoidosis in Children

Author: Ralph Epaud, Baptiste Morel, Nadia Nathan, Harriet Corvol, Chiara Sileo, Patrick Tounian, Hubert Ducou Le Pointe, and Eléonore Blondiaux
Subjects: Male, medicine.medical_specialty, Adolescent, Sarcoidosis, Biopsy, Digestive System Diseases, Hepatosplenomegaly, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Abdomen, Humans, Medicine, Child, Lymph node, Retrospective Studies, Splenic Diseases, Ultrasonography, medicine.diagnostic_test, business.industry, Gastroenterology, Infant, Retrospective cohort study, medicine.disease, medicine.anatomical_structure, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, 030211 gastroenterology & hepatology, Lymph Nodes, Radiology, Splenic disease, medicine.symptom, Tomography, X-Ray Computed, business, Calcification
Abstract: Objectives Sarcoidosis is a multisystem, granulomatous inflammatory disease affecting both pediatric and adult patients. So far in children, very few radiological descriptions of abdominal sarcoidosis manifestations have been reported. The present study describes the frequency and the appearance of abdominal radiologic manifestations in pediatric patients with histologically proven sarcoidosis. Methods We reviewed retrospectively all of the radiological examinations of 22 patients ages 1 to 15 years at diagnosis with proven sarcoidosis evaluated in a university pediatric hospital between 1994 and 2014. The locations of biopsies and the angiotensin-converting enzyme level were reported. The size, shape, and parenchymal homogeneity of the liver and spleen, the presence of abdominal lymph nodes, and abnormalities of the gastrointestinal tract were tabulated. Results The study included 22 children (mean age: 9.9 ± 2.8 years). The liver was the most frequent location of biopsy (12/22), even without radiological involvement. Abdominal manifestations were present in 11 of 22 children with sarcoidosis. Hepatomegaly was the most frequent abnormality, reported in 8 of 11 cases either homogeneous (n = 7) or nodular (n = 1). Homogeneous lymph node enlargement was noted in 6 of 11 cases and splenomegaly in 4 of 11 cases. No calcification was observed. All patients with initial abdominal sarcoidosis had simultaneous thoracic involvement. Conclusions Abdominal manifestations in children sarcoidosis are frequent but often nonspecific. Nodular hepatosplenomegaly is rare. All of our patients with abdominal abnormalities had a more specific associated thoracic involvement. Awareness of this association could assist the clinicians in assessing the initial diagnosis of abdominal sarcoidosis in children.
Published: 2016
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41. First Wave of COVID-19 in French Patients with Cystic Fibrosis

Author: S. Ramel, Martine Reynaud Gaubert, Astrid Kemgang, Harriet Corvol, Véronique Houdouin, Isabelle Durieu, Pierre-Régis Burgel, Marine Revillion, Lydie Lemonnier, Laurence Weiss, Sandra de Miranda, Raphaël Chiron, Marie-Laure Dalphin, A. Prevotat, Pierre-Yves Boëlle, Jean-Christophe Dubus, Loïc Guillot, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Hôpital Foch [Suresnes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Pneumologie et Allergie - Hôpital Nord [Marseille], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département des maladies respiratoires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Gestionnaire, Hal Sorbonne Université
Subjects: medicine.medical_specialty, Cystic Fibrosis, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, lcsh:Medicine, Cystic fibrosis, Asymptomatic, Article, law.invention, Serology, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, Diabetes mellitus, Oxygen therapy, Medicine, 030212 general & internal medicine, education, education.field_of_study, Lung, SARS-CoV-2, business.industry, lcsh:R, COVID-19, General Medicine, acute respiratory distress syndrome, medicine.disease, lung transplant, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030228 respiratory system, medicine.symptom, business
Abstract: Viral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs, 1 had negative RT-PCR but typical COVID-19 signs on a CT scan, and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9&ndash, 60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes (n = 19, 61.3%), and a mild lung disease (n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV1) &gt, 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever (n = 22, 78.6%), fatigue (n = 14, 50%), and increased cough (n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely.
Published: 2020
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42. P048 Pseudomonas aeruginosa lung infection in paediatric cystic fibrosis patients: risk factors and impact on lung function

Author: Loïc Guillot, Julie Mésinèle, Pierre-Yves Boëlle, Manon Ruffin, and Harriet Corvol
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Pseudomonas aeruginosa, Lung infection, medicine.disease_cause, medicine.disease, Gastroenterology, Cystic fibrosis, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, business, Lung function
Published: 2020
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43. Down syndrome and pulmonary hemosiderosis: an under-recognized association

Author: Sophie Leyronnas, Pierrick Cros, Philippe Reix, Antoine Deschildre, Caroline Thumerelle, Harriet Corvol, Françoise Troussier, Annick Clement, Sylvie Roullaud, Jessica Taytard, Michael Fayon, Marie-Catherine Renoux, Jacques de Blic, Guillaume Thouvenin, Caroline Perisson, Isabelle Gibertini, Rola Abou Taam, Aude Forgeron, Marc Lubrano Lavadera, Ralph Epaud, Véronique Houdouin, Aurelia Alimi, Jocelyne Derelle, Nadia Nathan, and Aimé Ravel
Subjects: Autoimmune disease, medicine.medical_specialty, Down syndrome, Lung, business.industry, Interstitial lung disease, Pulmonary hemosiderosis, Hemosiderosis, Disease, medicine.disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, Internal medicine, medicine, 030212 general & internal medicine, Risk factor, business
Abstract: Introduction: Pulmonary hemosiderosis is a rare cause of interstitial lung disease in children. The French experience had previously highlighted that 20% of the 25 included children also had Down syndrome (DS). In this study populations, the main features of the patients with hemosiderosis were unspecific stigmata of autoimmune disease. This study aims to investigate the relationships between pulmonary hemosiderosis and DS. Material and methods: Patients with pulmonary hemosiderosis followed is one of RespiRare network and younger than 20 years old at diagnosis were selected. The following data were collected : DS status, clinical, biological, functional, and radiological findings. Results: Nine of the 34 included patients (26%) had DS. They were a girl predominance (72%) in the non-DS group, and a male predominance in the DS group (56%). The mean age at the diagnosis was 3.80±3.30 with no significant difference between DS and non-DS patients. DS patients tended to present a more severe form of the disease with more dyspnoea (p=0.03) and more pulmonary arterial hypertension (PAH) (p=0.0003). The 3 (9%) patients who died were DS patients (p=0.0003). Discussion and conclusions: DS seem to be a risk factor for hemosiderosis. Hemosiderosis in DS patients is more severe at presentation, and at follow-up. Several hypotheses can be proposed for such association: an increased fragility of the lung capillary, a higher susceptibility to autoimmune lesions, and a higher risk of chronic hypoxia, leading to PAH. In DS, hemosiderosis should be considered in patients with anaemia of unknown origin.
Published: 2018
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44. Prophylactic azithromycin in patients with primary ciliary dyskinesia

Author: Estelle Escudier, Alix Massiot, Aline Tamalet, Harriet Corvol, Annick Clement, Guillaume Thouvenin, and Nicole Beydon
Subjects: 0301 basic medicine, medicine.medical_specialty, Exacerbation, Respiratory tract infections, 010405 organic chemistry, business.industry, Retrospective cohort study, Disease, medicine.disease, Azithromycin, 01 natural sciences, 0104 chemical sciences, 03 medical and health sciences, 030104 developmental biology, Antibiotic resistance, Internal medicine, otorhinolaryngologic diseases, medicine, Respiratory system, business, Primary ciliary dyskinesia, medicine.drug
Abstract: Introduction: Primary ciliary dyskinesia (PCD) is a rare genetic disease characterized by abnormalities in ciliary function, responsible for abnormal mucus clearance and repeated respiratory tract infections. The potential benefit of macrolide antibiotics has been evaluated in variety of chronic respiratory diseases. The efficacy of long-term azithromycine (AZT) has never been studied in PCD patients. Aim: The aim of this retrospective study was to investigate the effect of long-term AZT on the decrease in annual number of pulmonary exacerbations in children with PCD. Materials and Methods: All of our patients followed in our Pediatric center and who received low dose of AZT for more than 6 months were included. The clinical data (rate of pulmonary exacerbations, lung function analyses, ENT symptoms and changes in the airways bacterial colonizations) were collected from 1 year before and up to 5 years after the initiation of the AZT treatment. Results: A total of 31 children were included (11 years +/- 4 years). After 1 year, we observed a significant reduction in the annual number of pulmonary exacerbations (on average 1.7 +/- 2.7 exacerbations per year before treatment versus 0.5 +/- 1 exacerbation per year after 1 year of treatment) and a significant improvement in ENT symptoms. However, the lung function decline was not modified. No difference in the airways colonizations by pathogens, nor emerging antibiotic resistance were observed during the treatment. Conclusion: Our study showed a clinical improvement of PCD children treated by long term AZT. Those results must be confirmed by a larger multicenter study, such as the one currently conducted by the BEAT PCD group.
Published: 2018
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45. SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis

Author: Harriet Corvol, Julie Mésinèle, Isman-Hassan Douksieh, Lisa J. Strug, Pierre-Yves Boëlle, and Loïc Guillot
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Single-nucleotide polymorphism, Cystic fibrosis, lung, cystic fibrosis, Ivacaftor, 03 medical and health sciences, SLC26A9, Internal medicine, medicine, Pharmacology (medical), Original Research, Pharmacology, Lung, business.industry, lcsh:RM1-950, medicine.disease, gene modifier, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, medicine.anatomical_structure, individualized medicine, Pharmacogenomics, Cohort, pharmacogenetic, ivacaftor, Personalized medicine, business, Pharmacogenetics, medicine.drug
Abstract: Ivacaftor is a drug used to treat cystic fibrosis (CF) patients carrying specific gating CFTR mutations. Interpatient variability in the lung response has been shown to be partly explained by rs7512462 in the Solute Carrier Family 26 Member 9 (SLC26A9) gene. In an independent and larger cohort, we aimed to evaluate whether SLC26A9 variants contribute to the variability of the lung phenotype and if they influence the lung response to ivacaftor. We genotyped the French CF Gene Modifier Study cohort (n = 4,840) to investigate whether SLC26A9 variants were involved in the lung phenotype heterogeneity. Their influence in the response to ivacaftor was tested in the 30 treated patients who met the inclusion criteria: older than 6 years of age, percent-predicted forced expiratory volume measured in 1 s (FEV1pp) in the 3 months before treatment initiation ranging between 40 and 90%. Response to treatment was determined by the change in FEV1pp from baseline, averaged in 15–75 days, and the 1st-year post-treatment. We observed that SLC26A9 variants were not associated with lung function variability in untreated patients and that gain of lung function in patients treated with ivacaftor was similar to clinical trials. We confirmed that rs7512462 was associated with variability in ivacaftor-lung response, with a significant reduction in lung function improvement for patients with the C allele. Other SLC26A9 SNPs also contributed to the ivacaftor-response. Interindividual variability in lung response to ivacaftor is associated with SLC26A9 variants in French CF patients. Pharmacogenomics and personalized medicine will soon be part of CF patient care.
Published: 2018
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46. Opposite Expression of Hepatic and Pulmonary Corticosteroid-Binding Globulin in Cystic Fibrosis Patients

Author: Anastasia Tchoukaev, Jessica Taytard, Nathalie Rousselet, Carine Rebeyrol, Dominique Debray, Sabine Blouquit-Laye, Marie-Pierre Moisan, Aline Foury, Loic Guillot, Harriet Corvol, Olivier Tabary, Philippe Le Rouzic, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Pneumologie pédiatrique [CHU Trousseau], Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and ProdInra, Migration
Subjects: 0301 basic medicine, medicine.medical_specialty, corticosteroid-binding globulin, cystic fibrosis, glucocorticoids, liver, lung, Globulin, [SDV]Life Sciences [q-bio], Context (language use), [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, pcr, Western blot, Transcortin, glucocorticoïde, Internal medicine, Medicine, Pharmacology (medical), mucoviscidose, corticostéroïde plasmique, fibrose cystique, Pharmacology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Lung, biology, medicine.diagnostic_test, business.industry, Pulmonary inflammation, lcsh:RM1-950, Elastase, cirrhose du foie, santé humaine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, biology.protein, inflammation pulmonaire, business, 030217 neurology & neurosurgery
Abstract: International audience; Cystic fibrosis (CF) is characterized by a chronic pulmonary inflammation. In CF, glucocorticoids (GC) are widely used, but their efficacy and benefit/risk ratio are still debated. In plasma, corticosteroid-binding globulin (CBG) binds 90% of GC and delivers them to the inflammatory site. The main goal of this work was to study CBG expression in CF patients in order to determine whether CBG could be used to optimize GC treatment. The expression of CBG was measured in liver samples from CF cirrhotic and non-CF cirrhotic patients by qPCR and Western blot and in lung samples from non-CF and CF patients by qPCR. CBG binding assays with H-3-cortisol and the measurement of the elastase/alpha 1-antitrypsin complex were performed using the plasmas. CBG expression increased in the liver at the transcript and protein level but not in the plasma of CF patients. This is possibly due to an increase of plasmatic elastase. We demonstrated that pulmonary CBG was expressed in the bronchi and bronchioles and its expression decreased in the CF lungs, at both levels studied. Despite the opposite expression of hepatic and pulmonary CBG in CF patients, the concentration of CBG in the plasma was normal. Thus, CBG might be useful to deliver an optimized synthetic GC displaying high affinity for CBG to the main inflammatory site in the context of CF, e.g., the lung.
Published: 2018
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47. Pulmonary hemosiderosis in children with Down syndrome: a national experience

Author: Aurelia Alimi, Jessica Taytard, Rola Abou Taam, Véronique Houdouin, Aude Forgeron, Marc Lubrano Lavadera, Pierrick Cros, Isabelle Gibertini, Jocelyne Derelle, Antoine Deschildre, Caroline Thumerelle, Ralph Epaud, Philippe Reix, Michael Fayon, Sylvie Roullaud, Françoise Troussier, Marie-Catherine Renoux, Jacques de Blic, Sophie Leyronnas, Guillaume Thouvenin, Caroline Perisson, Aimé Ravel, Annick Clement, Harriet Corvol, Nadia Nathan, for the French RespiRare® group, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] (MaMEA Necker), 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 sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), RespiRare - Centre pédiatrique de pneumologie et de référence pour les maladies pulmonaires rares [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pédiatrie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Département de pneumologie pédiatrique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Département de pneumologie pédiatrique [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de pédiatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de pneumologie pédiatrique [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Département de pneumologie pédiatrique [CHU Créteil] (RespiRare), Centre Hospitalier Universitaire de Lille (CHU de Lille), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), 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), Département de pneumologie pédiatrique [CHU Lyon], Centre Hospitalier Universitaire de Lyon (CHU Lyon), Département de pneumologie pédiatrique [CHU Bordeaux], CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pneumologie pédiatrique [CH Angoulême], Centre Hospitalier d'Angoulême (CH Angoulême), Département de pneumologie pédiatrique [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Sorbonne Université (SU), Institut Jérôme Lejeune, Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), French RespiRare® group, ANR-10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010), European Project: 305653,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,CHILD-EU(2012), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), 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), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Bernardo, Elizabeth, Cohortes - Cohorte nationale maladies rares - - RADICO2010 - ANR-10-COHO-0003 - COHO - VALID, Orphans Unite: chILD better together –European Management Platform for Childhood Interstitial Lung Diseases - CHILD-EU - - EC:FP7:HEALTH2012-12-01 - 2016-11-30 - 305653 - VALID, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Maladies génétiques d'expression pédiatrique (U933), RespiRare - Centre pédiatrique de pneumologie et de référence pour les maladies pulmonaires rares [AP-HP Hôpital Armand-Trousseau], AP-HP Hôpital Armand-Trousseau [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Département de Pédiatrie [CH Le Mans], Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier d'Angoulême, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Sorbonne Universités, Physiopathologie des maladies génétiques d'expression pédiatrique, and ANR-10-COHO-03/10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010)
Subjects: Lung Diseases, Male, Pediatrics, Down syndrome, lcsh:Medicine, Autoimmunity, 0302 clinical medicine, Medicine, Celiac disease, Pharmacology (medical), Young adult, Child, Children, Genetics (clinical), education.field_of_study, Interstitial lung disease, General Medicine, 3. Good health, medicine.anatomical_structure, Child, Preschool, Female, medicine.symptom, Vasculitis, Adult, medicine.medical_specialty, Hemosiderosis, Adolescent, Hypertension, Pulmonary, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pulmonary hypertension, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030225 pediatrics, Humans, education, Lung, business.industry, Research, lcsh:R, Infant, Newborn, Infant, Hypoxia (medical), medicine.disease, Pulmonary hemosiderosis, 030228 respiratory system, business, Lung Diseases, Interstitial
Abstract: Background Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS. Methods Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients’ data were compared. Results A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution. Conclusions DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease. Electronic supplementary material The online version of this article (10.1186/s13023-018-0806-6) contains supplementary material, which is available to authorized users.
Published: 2018
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48. Gas exchanges in children with cystic fibrosis or primary ciliary dyskinesia: A retrospective study

Author: Aline Tamalet, Estelle Escudier, Priscilla Boizeau, Camille Aupiais, Jessica Taytard, Guillaume Thouvenin, Harriet Corvol, Nicole Beydon, Marilyn Fuger, Service de physiologie, unité fonctionnelle d’explorations respiratoires [CHU Trousseau], 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), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sciences de l’information au service de la médecine personnalisée (CRC - Inserm U1138), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Service de génétique et embryologie médicales [CHU Trousseau], Hôpital Robert Debré Paris, Hôpital Robert Debré, 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) (APHP)-CHU Trousseau [APHP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Pneumologie Pédiatrique [CHU Trousseau], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Male, Cystic Fibrosis, Physiology, Vital Capacity, Cystic fibrosis, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Forced Expiratory Volume, MESH: Child, 030212 general & internal medicine, Longitudinal Studies, Child, MESH: Longitudinal Studies, Lung, Primary ciliary dyskinesia, medicine.diagnostic_test, General Neuroscience, MESH: Infant, Child, Preschool, Female, circulatory and respiratory physiology, Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Adolescent, MESH: Cystic Fibrosis, MESH: Blood Gas Analysis, MESH: Forced Expiratory Volume, 03 medical and health sciences, Internal medicine, Mixed linear model, medicine, otorhinolaryngologic diseases, Humans, MESH: Lung, Pulmonary gas exchange, Retrospective Studies, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Bronchiectasis, MESH: Humans, business.industry, Kartagener Syndrome, MESH: Child, Preschool, Infant, Retrospective cohort study, MESH: Retrospective Studies, MESH: Vital Capacity, medicine.disease, MESH: Male, respiratory tract diseases, 030228 respiratory system, MESH: Kartagener Syndrome, Childhood respiratory disease, Blood Gas Analysis, Clinical aspects of cystic fibrosis, MESH: Spirometry, business, MESH: Pulmonary Gas Exchange, MESH: Female
Abstract: International audience; Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) both entail bronchiectasis and pulmonary impairment as measured using spirometry, during childhood. We aimed at looking whether blood gas exchanges progressed differently between CF and PCD children in a retrospective study of repeated measurements. Comparisons between groups (Wilcoxon-Mann-Whitney and Chi-squared tests) and a mixed linear model, adjusted for age, evaluated associations between diseases and PaO2, PaCO2, or PaO2-PaCO2 ratio.Among 42 PCD and 73 CF children, 62% and 59% had respectively bronchiectasis (P = 0.75). Spirometry and blood gases were similar at inclusion (PaO2 median [IQR] PCD −1.80 [−3.40; −0.40]; CF −1.80 [−4.20; 0.60] z-scores; P = 0.72). PaO2 and PaO2-PaCO2 ratio similarly and significantly decreased with age in both groups (P
Published: 2018
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49. Biomarkers in Interstitial lung diseases

Author: Serge Amselem, Nadia Nathan, Annick Clement, and Harriet Corvol
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pulmonary Surfactant-Associated Proteins, Translational research, Idiopathic pulmonary fibrosis, High morbidity, Disease severity, medicine, Humans, Chitinase-3-Like Protein 1, Child, Intensive care medicine, Inflammation, Heterogeneous group, Lung, business.industry, Mucin-1, respiratory system, medicine.disease, Mucin-5B, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Patient management, medicine.anatomical_structure, Blood biomarkers, Chemokines, CC, Matrix Metalloproteinase 7, Pediatrics, Perinatology and Child Health, Immunology, Lung Diseases, Interstitial, business, Biomarkers
Abstract: Interstitial lung diseases (ILD)s represent a heterogeneous group of rare respiratory disorders, mostly chronic and associated with high morbidity and mortality. They are complex diseases that remain, in children, largely underdiagnosed and difficult to manage. Therefore, identification of biomarkers, which could be used for ILD diagnosis, measurements of disease severity and progression, and responsiveness to treatments, is a major challenge for clinical practice and for translational research. The present review focuses on blood biomarkers and provides an overview on the current information on molecular parameters of interest for ILD patient management.
Published: 2015
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50. MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology

Author: Olivier Tabary, Nathalie Rousselet, Philippe Le Rouzic, Florence Sonneville, Harriet Corvol, Sabine Blouquit-Laye, Manon Ruffin, Christelle Coraux, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), and Tabary, Olivier
Subjects: 0301 basic medicine, Science, General Physics and Astronomy, Cystic fibrosis, General Biochemistry, Genetics and Molecular Biology, Article, ANO1, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Medicine, lcsh:Science, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, biology, business.industry, Calcium channel, General Chemistry, Anatomy, respiratory system, medicine.disease, Mucus, Cystic fibrosis transmembrane conductance regulator, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Chloride channel, Cancer research, biology.protein, lcsh:Q, business, Anoctamin-1, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Cystic fibrosis results from reduced cystic fibrosis transmembrane conductance regulator protein activity leading to defective epithelial ion transport. Ca2+-activated Cl− channels mediate physiological functions independently of cystic fibrosis transmembrane conductance regulator. Anoctamin 1 (ANO1/TMEM16A) was identified as the major Ca2+-activated Cl− channel in airway epithelial cells, and we recently demonstrated that downregulation of the anoctamin 1 channel in cystic fibrosis patients contributes to disease severity via an unknown mechanism. Here we show that microRNA-9 (miR-9) contributes to cystic fibrosis and downregulates anoctamin 1 by directly targeting its 3′UTR. We present a potential therapy based on blockage of miR-9 binding to the 3′UTR by using a microRNA target site blocker to increase anoctamin 1 activity and thus compensate for the cystic fibrosis transmembrane conductance regulator deficiency. The target site blocker is tested in in vitro and in mouse models of cystic fibrosis, and could be considered as an alternative strategy to treat cystic fibrosis., Downregulation of the anoctamin 1 calcium channel in airway epithelial cells contributes to pathology in cystic fibrosis. Here the authors show that microRNA-9 targets anoctamin 1 and that inhibiting this interaction improves mucus dynamics in mouse models.
Published: 2017
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