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1. Associations between respiratory pathogens and lung function in primary ciliary dyskinesia: cross-sectional analysis from the PROVALF-PCD cohort

Author: Bruna Rubbo, Avni Kant, Kewei Zhang, Annalisa Allegorico, Simona Basilicata, Mieke Boon, Melissa Borrelli, Claudia Calogero, Siobhán B. Carr, Mary Carroll, Carolina Constant, Silvia Castillo Corullón, Harriet Corvol, Renato Cutrera, Stefanie Dillenhöfer, Nagehan Emiralioglu, Ela Eralp, Sanem Eryilmaz Polat, Laura Gardner, Yasemin Gokdemir, Amanda Harris, Claire Hogg, Bulent Karadag, Helene Kobbernagel, Cordula Koerner-Rettberg, Panayiotis Kouis, Natalie Lorent, Markella Marcou, June K. Mathin, Vendula Martinu, Antonio Moreno-Galdó, Lucy Morgan, Kim G. Nielsen, Heymut Omran, Ugur Ozcelik, Petr Pohunek, Johanna Raidt, Phil Robinson, Sandra Rovira-Amigo, Francesca Santamaria, Anne Schlegtendal, Aline Tamalet, Guillaume Thouvenin, Nicola Ullmann, Woolf Walker, Panayiotis Yiallouros, Claudia E. Kuehni, Philipp Latzin, Nicole Beydon, and Jane S. Lucas
Subjects: Medicine
Abstract: Introduction Respiratory pathogens are frequently isolated from airway samples in primary ciliary dyskinesia (PCD) patients. Few studies have investigated associations between these pathogens and lung function, with current management based on evidence from cystic fibrosis. We investigated the association between commonly isolated respiratory pathogens and lung function in PCD patients. Methods Using a cross-sectional design, we prospectively collected clinical and concurrent microbiology data from 408 participants with probable or confirmed PCD, aged ≥5 years, from 12 countries. We used Global Lung Function Initiative 2012 references to calculate forced expiratory volume in 1 s (FEV1) z-scores. For 351 patients (86%) with complete data, we assessed the association of the four most frequently isolated pathogens with lung function by fitting multilevel linear models with country as random intercept, adjusted for age at diagnosis, age at lung function, use of antibiotic prophylaxis and body mass index z-scores. Results Individuals with Pseudomonas aeruginosa growth in culture had significantly lower FEV1 z-scores (β= −0.87, 95% CI −1.40– −0.34), adjusted for presence of Haemophilus influenzae, methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae, and for covariates. When stratified by age, associations remained strong for adults but not for children. Results were similar when ciliary defects by transmission electron microscopy were included in the models and when restricting analysis to only confirmed PCD cases. Conclusions We found that P. aeruginosa was associated with worse lung function in individuals with PCD, particularly adults. These findings suggest that it is prudent to aim for P. aeruginosa eradication in the first instance, and to treat exacerbations promptly in colonised patients.
Published: 2024
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2. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Author: Chiara Olcese, Mitali P. Patel, Amelia Shoemark, Santeri Kiviluoto, Marie Legendre, Hywel J. Williams, Cara K. Vaughan, Jane Hayward, Alice Goldenberg, Richard D. Emes, Mustafa M. Munye, Laura Dyer, Thomas Cahill, Jeremy Bevillard, Corinne Gehrig, Michel Guipponi, Sandra Chantot, Philippe Duquesnoy, Lucie Thomas, Ludovic Jeanson, Bruno Copin, Aline Tamalet, Christel Thauvin-Robinet, Jean- François Papon, Antoine Garin, Isabelle Pin, Gabriella Vera, Paul Aurora, Mahmoud R. Fassad, Lucy Jenkins, Christopher Boustred, Thomas Cullup, Mellisa Dixon, Alexandros Onoufriadis, Andrew Bush, Eddie M. K. Chung, Stylianos E. Antonarakis, Michael R. Loebinger, Robert Wilson, Miguel Armengot, Estelle Escudier, Claire Hogg, UK10K Rare Group, Serge Amselem, Zhaoxia Sun, Lucia Bartoloni, Jean-Louis Blouin, and Hannah M. Mitchison
Subjects: Science
Abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease resulting in reduced mucus clearance and impaired lung function. Here, the authors show that mutations in PIH1D3 are responsible for an X-linked form of PCD, affecting assembly of a subset of inner arm dyneins.
Published: 2017
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3. 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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4. High Nasal Nitric Oxide, Cilia Analyses, and Genotypes in a Retrospective Cohort of Children with Primary Ciliary Dyskinesia

Author: Marie Legendre, Guillaume Thouvenin, Jessica Taytard, Marguerite Baron, Muriel Le Bourgeois, Aline Tamalet, Rahma Mani, Gregory Jouvion, Serge Amselem, Estelle Escudier, Nicole Beydon, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), UF de Génétique moléculaire [CHU Trousseau], 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), Centre National de Référence des Maladies Respiratoires Rares, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Sousse, 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), and Couvet, Sandrine
Subjects: Pulmonary and Respiratory Medicine, MESH: Amino Acids, Genotype, bronchiectasis, [SDV]Life Sciences [q-bio], genetic analysis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Nitric Oxide, MESH: Genotype, MESH: Cilia, MESH: Child, Humans, Cilia, Amino Acids, Child, Retrospective Studies, MESH: Humans, Kartagener Syndrome, MESH: Retrospective Studies, ultrastructure, [SDV] Life Sciences [q-bio], cilia motility, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Nitric Oxide, MESH: Kartagener Syndrome, MESH: Ciliary Motility Disorders, Ciliary Motility Disorders
Abstract: International audience; Rationale: Although children with primary ciliary dyskinesia (PCD) typically have low nasal nitric oxide (nNO), some children with indisputable PCD may have unexplained high nNO concentrations. Objectives: To look for relationships between nNO measures and genetic findings (and cilia motility or ultrastructure when available) in children with PCD with known genotypes. Methods: We retrospectively studied 73 children with PCD (median age, 9.5 [range, 2.1-18.2] yr). nNO was the mean value of a plateau reached while the velum was closed (nNO-VC; threshold, 77 nl ⋅ min-1) or was calculated as the average of five peaks obtained during tidal breathing (threshold, 40 nl ⋅ min-1). Ciliary beat was classified as either motile (including dyskinetic pattern) or immotile, depending on whether motility was present or absent in all cilia, or as a mixture of motile and immotile cilia. Genotypes were classified as pathogenic mutations in genes known to be associated with high nNO (mild genotype), biallelic truncating mutations in other genes (severe mutations), or putative hypomorphic pathogenic mutations (missense, single amino acid deletion, or moderate splicing mutations) in at least one allele believed to be possibly associated with residual production of a functional protein. Results: nNO was above the discriminant threshold in 16 of 73 (21.9%) children (11 nNO-VC and 5 nNO during tidal breathing). High nNO was less frequent in children with severe mutations (2 of 42) than in those with mild genotypes (7 of 10) or at least one hypomorphic mutation (7 of 21) (P
Published: 2022
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5. Dyskinésies ciliaires primitives de l’enfant

Author: Sylvain Blanchon, Marie Legendre, J.-F. Papon, Aline Tamalet, Estelle Escudier, Nicole Beydon, and Guillaume Thouvenin
Subjects: 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Pediatrics, Perinatology and Child Health, 030212 general & internal medicine
Abstract: Resume Les dyskinesies ciliaires primitives (DCP) sont des maladies genetiques rares dues a des anomalies de structure et/ou de fonction des cils mobiles, responsables d’un defaut d’epuration muco-ciliaire. Ces dysfonctions ciliaires conduisent a des infections chroniques des voies aeriennes superieures et inferieures, de debut possiblement neonatal. L’evolution, de gravite variable, se fait vers une rhinosinusite chronique parfois invalidante et des bronchiectasies progressives, mais l’esperance de vie est consideree comme peu diminuee. Environ la moitie des patients presentent des anomalies de lateralisation des visceres pouvant alors s’inscrire dans la triade du syndrome de So (sinusite chronique, bronchiectasies, situs inversus). Une infertilite masculine est possible, par mobilite anormale du flagelle des spermatozoides dont la structure interne est tres proche de celle des cils mobiles. Le diagnostic repose sur la mesure du debit nasal de monoxyde d’azote et l’analyse de la fonction et de l’ultrastructure des cils respiratoires. La genetique des DCP est complexe du fait de l’heterogeneite des anomalies ciliaires et du grand nombre de genes impliques (45 genes impliques a ce jour). Les patients requierent un suivi multidisciplinaire regulier, clinique, microbiologique, fonctionnel et radiologique. La prise en charge au long court repose principalement sur le drainage nasal et bronchique quotidien et l’antibiotherapie, permettant de reduire la morbidite et de proteger le capital pulmonaire des enfants atteints de DCP.
Published: 2020
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6. Breath holding and tidal breathing nasal NO to screen children for Primary Ciliary Dyskinesia

Author: Aline Tamalet, Estelle Escudier, Nicole Beydon, Guillaume Thouvenin, Marie Legendre, 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), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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], 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 génétique et embryologie médicales [CHU Trousseau], Gestionnaire, Hal Sorbonne Université, 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], and UF de Génétique moléculaire [CHU Trousseau]
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Nitric Oxide, Gastroenterology, Bronchiectasis & Primary Ciliary Dyskinesia, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Tidal breathing, medicine, Humans, In patient, Child, Primary ciliary dyskinesia, Retrospective Studies, Alternative methods, business.industry, Kartagener Syndrome, Exhalation, Gold standard (test), medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Clinical Practice, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030228 respiratory system, Breath Tests, Child, Preschool, Pediatrics, Perinatology and Child Health, Nitric Oxide (NO), business
Abstract: International audience; Nasal Nitric Oxide (nNO) measurement is recommended to screen for Primary Ciliary Dyskinesia (PCD) in subjects with suggestive history and symptoms. Clinical use of alternative methods (ie breath hold (BH), tidal breathing (TB)) in children unable to perform the gold standard slow Exhalation against a Resistance (ER) method has not been sufficiently evaluated. We extracted retrospectively (2013-2019) 454 files (374 subjects) containing nNO results. Median [IQR] age at inclusion was 7.0 [4.7 - 11.0] years, 105 (28.1%) children were younger than 5 years. ER or BH methods were more frequently mastered by children older than 5 years compared to younger children (69.4% and 52.7% versus 21% and 5.6%, respectively, P < 0.0001), the latter succeeding only in TB measurement in 77.4% of cases. In 130 files with both ER and BH measurements (nNO-ER and nNO-BH), nNO-BH was 102 [96.2;108.3]% that of nNO-ER. In 175 files including nNO-ER and nNO-TB measurements, nNO-TB was 64.4 [IQR: 53.7;80.4]% that of nNO-ER with an excellent correlation between nNO values (r = 0.94 [95%CI 0.91;0.95]; P
Published: 2021
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7. [Obstructive Sleep Apnea in Children: A Team effort!]

Author: Mai-Khanh, Lê-Dacheux, Guillaume, Aubertin, Catherine, Piquard-Mercier, Sébastien, Wartelle, Bertrand, Delaisi, Jean-Luc, Iniguez, Aline, Tamalet, Isabelle, Mohbat, Nicolas, Rousseau, Marie-Paule, Morisseau-Durand, and Aurelie, Majourau-Bouriez
Subjects: Interdisciplinary treatment, medicine.medical_specialty, Sleep Apnea, Obstructive, Health professionals, business.industry, General Medicine, medicine.disease, Obstructive sleep apnea, Adenoidectomy, Quality of life (healthcare), Multidisciplinary approach, Care pathway, Long term outcomes, Quality of Life, Medicine, Humans, Rapid maxillary expansion, business, Intensive care medicine, Child, Sleep, Tonsillectomy
Abstract: Obstructive Sleep Apnea (OSA) in children, which has a multifactorial origin, can lead, if not treated, to severe medical complications, growth disturbances, behavioural changes and reduced quality of life. Nowadays, it is underdiagnosed whereas early screening, diagnosis and interdisciplinary treatment are essential. Furthermore, many families and health professionals do not often know where to go when there is suspicion of OSA for a child. Orthodontists are uniquely positioned to screen, to refer to the appropriate specialist and to treat, if needed, patients who may be at high risk for OSA. The authors describe the synergistic means to screen, diagnose and treat paediatric OSA in a collaborative and interactive approach between ENT, orthodontists, pneumo-allergologists, sleep physicians, endocrinologists, orofacial myo-functional therapists and speech therapists. These means which are clinically illustrated in this paper fit the guidelines which have been recently published as white papers by official professional specialists organisations involved in paediatric OSA treatment (AAPD, AAO, FFO, SFORL, SFRMS…). The development of multidisciplinary teams gathering specialists who are conscious about the mutual benefits of the specialties involved in paediatric OSA should contribute to optimize the child treatment care pathway and the short, mid and long term outcomes.
Published: 2020

8. Relevance of nasal nitric oxide measurements using tidal breathing method for screening primary ciliary dyskinesia in young children

Author: Aline Tamalet, Estelle Escudier, Gregory Jouvion, Nicole Beydon, Guillaume Thouvenin, and Marie Legendre
Subjects: medicine.medical_specialty, business.industry, First line, Retrospective cohort study, medicine.disease, Gastroenterology, Nitric oxide, chemistry.chemical_compound, Testing protocols, Dyskinesia, chemistry, Internal medicine, Tidal breathing, medicine, medicine.symptom, Ciliary beating, business, Primary ciliary dyskinesia
Abstract: Background: North American standardised testing protocols assume that only nasal Nitric Oxide (nNO) measured during expiration against a mouth resistance (ExRe) in children older than 5 years is a reliable tool for diagnosis of Primary Ciliairy Dyskinesia (PCD). Objectives: To establish the relevance of tidal breathing (TB) nNO measurement as a first line test in young children. Methods: Monocenter retrospective study (2013 - 2019) based on the records of children seen for suspicion of PCD. nNOExRe and nNOTB were measured using CLD 88 sp (EcoPhysics, Suisse). Results: Nasal NO measurement was possible on 460 occasions in 382 children (median [IQR] (range) age of 7.1 [4.8 to 11.1](0.1 to 19.4) years, 167 (43.7%) females). Recorded numbers of nNOExRe and nNOTB were 247 (53%) and 355 (77%); respectively, with 158 (34%) nNOTB on isolation. One hundred and five children 5 years or less performed 24 (19%) nNOExRe and 119 (94%) nNOTB. Among the 81 children with only nNOTB result and based on all available investigations, PCD diagnosis was excluded (n=58, nNOTB 298 [199;391]ppb), confirmed or very probable but pending (n=12 and n=3, nNOTB 42 [28;69]ppb), or unknown (n=8, nNOTB 129 [31;239]ppb). Among children with excluded versus confirmed / pending PCD diagnosis, frequencies of ciliary beat study, electron microscopy, and genetic testing were 15 (26%) versus 9 (60%), 3 (20%) versus 8 (53%), and 0 versus 8 (53%), respectively. Conclusion: In children less than 5 years, the success rate of nNOTB measurements was 94% and allowed stopping PCD workup in 74% of cases in children with medium-low clinical suspicion.
Published: 2020
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9. Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia

Author: Mathieu Bottier, Aline Tamalet, Jean-François Papon, Annick Clement, Guy Montantin, Marie Legendre, Serge Amselem, Catherine Faucon, André Coste, Nathalie Collot, Florence Dastot, Bruno Copin, Sylvain Blanchon, Marcel Filoche, Estelle Escudier, Bruno Louis, Laboratoire de physique de la matière condensée (LPMC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], 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)-CHU Trousseau [APHP], Centre Hospitalier Intercommunal de Créteil (CHIC), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'ORL [Créteil], Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
Subjects: Adult, Male, 0301 basic medicine, Candidate gene, Axoneme, Adolescent, Genotype, Video microscopy, Biology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Abnormal ciliary motility, Cilia, [PHYS.COND.CM-DS-NN]Physics [physics]/Condensed Matter [cond-mat]/Disordered Systems and Neural Networks [cond-mat.dis-nn], Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Primary ciliary dyskinesia, Microscopy, Video, Cilium, Infant, Newborn, Genetic disorder, High-Throughput Nucleotide Sequencing, Infant, Axonemal Dyneins, Middle Aged, medicine.disease, Molecular biology, Phenotype, DNA-Binding Proteins, Cytoskeletal Proteins, 030104 developmental biology, 030228 respiratory system, Child, Preschool, Mutation, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Female, [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], Ciliary Motility Disorders
Abstract: BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.MethodsWe prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).ResultsSixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.ConclusionQuantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.
Published: 2020
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10. TTC12 loss-of-function mutations cause primary Ciliary Dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella

Author: Lucie Thomas, Khaled Bouhouche, Marjorie Whitfield, Guillaume Thouvenin, Andre Coste, Bruno Louis, Claire Szymanski, Emilie Bequignon, Jean-François Papon, Manon Castelli, Michel Lemullois, Xavier Dhalluin, Valérie Drouin-Garraud, Guy Montantin, Sylvie Tissier, Philippe Duquesnoy, Bruno Copin, Florence Dastot, Sandrine Couvet, Anne-Laure Barbotin, Catherine Faucon, Isabelle Honore, Bernard Maitre, Nicole Beydon, Aline Tamalet, Nathalie Rives, France Koll, Estelle Escudier, Anne-Marie Tassin, Aminata Touré, Valérie Mitchell, Serge Amselem, Marie Legendre, Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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 de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biogenèse et Fonction de la Structure Centriolaire et Ciliaire (BIOCIL), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), 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), 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), Biomécanique & Appareil Respiratoire (BAR), 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), Service d'ORL [Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), IMRB - 'Biomechanics and Respiratory Apparatus' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Claude Huriez [Lille], CHU Lille, Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Charles Nicolle [Rouen], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, CHU Rouen, Normandie Université (NU), Hôpital Jeanne de Flandres, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies génétiques d'expression pédiatrique (U933), Normandie Université (NU)-Normandie Université (NU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Male, Axoneme, [SDV]Life Sciences [q-bio], primary ciliary dyskinesia, 0302 clinical medicine, hemic and lymphatic diseases, Child, Genetics (clinical), Primary ciliary dyskinesia, Cilium, Homozygote, Inner dynein arm, Middle Aged, Phenotype, Cell biology, Pedigree, [SDV] Life Sciences [q-bio], Flagella, Motile cilium, Sperm Motility, Female, CRISPR-Cas9, Ciliary Motility Disorders, Adult, dynein arm assembly, Dynein, Biology, Flagellum, Article, TTC12, 03 medical and health sciences, Young Adult, Genetics, medicine, Humans, Infertility, Male, Ciliate, cilia, Dyneins, Proteins, nutritional and metabolic diseases, biology.organism_classification, medicine.disease, sperm flagella, 030104 developmental biology, Sperm Tail, Mutation, 030217 neurology & neurosurgery
Abstract: International audience; Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate $Paramecium\ tetraurelia$ recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella.
Published: 2020
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11. Non-invasive CT screening for pulmonary arteriovenous malformations in children with confirmed hereditary hemorrhagic telangiectasia: Results from two pediatric centers

Author: Jean-Yves Rioux, Virginie Escabasse, Hubert Ducou Le Pointe, Suzanne Verlhac, Ralph Epaud, Florent Soubrier, Isabelle Hau, Manuela Vasile, Stéphanie Franchi-Abella, Nurcan Soysal, Marie-France Carette, Natascha Remus, Sarah Robert, Aline Tamalet, Céline Delestrain, and Mélanie Eyries
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, High-resolution computed tomography, medicine.diagnostic_test, business.industry, Mucocutaneous zone, Genetic disorder, Arteriovenous malformation, ACVRL1, Endoglin, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Dysplasia, hemic and lymphatic diseases, Pediatrics, Perinatology and Child Health, otorhinolaryngologic diseases, medicine, medicine.symptom, Telangiectasia, business, 030217 neurology & neurosurgery
Abstract: SummaryBackground Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM). Aim to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT). Methods parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast. Results between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy. Conclusion This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642–649. © 2017 Wiley Periodicals, Inc.
Published: 2017
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12. 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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13. 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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14. 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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15. Collaborateurs

Author: Grégoire, Benoist, Antoine, Bourrillon, Christophe, Delacourt, Christèle, Gras-Le Guen, Benoit, Billy (de), Agnès, Liard-Zmuda, Patrick, Tounian, François, Angoulvant, Jean-Baptiste, Arnoux, Frédéric, Auber, Guillaume, Aubertin, Georges, Audry, Stéphane, Auvin, Justine, Bacchetta, Martine, Balençon, Pascal, Barat, Marc, Bellaïche, Jacques, Beltrand, Etienne, Bidat, Arnaud, Bonnard, Claire, Bouvattier, Dominique, Bremond-Gignac, Frédéric, Brioude, Olivier, Brissaud, Jean-Claude, Carel, Ania, Carsin, Mireille, Castanet, Brigitte, Chabrol, Gérard, Chéron, Bertrand, Chevallier, Jacques, Cheymol, Pierre, Corre, Régis, Coutant, Laurianne, Coutier, Pierrick, Cros, Jean-Christophe, Cuvellier, Jean-Hugues, Dalle, Stéphane, Dauger, Céline, Delestrain, Amandine, Divaret-Chauveau, François, Doz, David, Drummond, Béatrice, Dubern, Sophie, Dugue, Thomas, Édouard, Brigitte, Fauroux, Albert, Faye, Pierre, Fayoux, Cyril, Flamant, Elisabeth, Fournier-Charrière, Virginie, Gandemer, Alexandra, Gauthier, Olivia, Gillion-Boyer, Lisa, Giovannini-Chami, Emmanuel, Grimprel, Alice, Hadchouel-Duvergé, Sébastien, Héritier, Christina, Ioan Iulia, Pierre-Henri, Jarreau, Etienne, Javouhey, Eric, Jeziorski, Elsa, Kermorvant, Béatrice, Kugener, François, Labarthe, André, Labbé, Géraldine, Labouret, Elise, Launay, Rémi, Laporte, Nicolas, Leboulanger, Joël, Lechevallier, Juliane, Léger, Stéphanie, Lejeune, Stéphanie, Leroux, Guillaume, Lezmi, Anne, Lienhardt-Roussie, Agnès, Linglart, Mathie, Lorrot, Natalie, Loundon, Jehanne, Malek, Christophe, Marguet, Aude, Marie Cardine, Laetitia, Martinerie, Emmanuel, Mas, Thierry, Merrot, Matthieu, Milh, Despina, Moshous, Pierre-Yves, Mure, Javotte, Nancy, Nadia, Nathan, Irene, Netchine, Marc, Nicolino, Richard, Nicollas, Sylvie, Odent, Caroline, Ovaert, Françoise, Paris, Laurent, Pasquier, Aurélie, Phulpin, Capucine, Picard, Georges, Picherot, Guillaume, Podevin, Michel, Polak, Philippe, Ravasse, Rachel, Reynaud, Sylvie, Rossignol, Sébastien, Rouget, Jean-Christophe, Rozé, Philippe, Sachs, Frédérique, Sauvat, Cyril, Schweitzer, Isabelle, Sermet-Gaudelus, Chantal, Stheneur, Isabelle, Talon, Aline, Tamalet, Maïté, Tauber, Jessica, Taytard, Jean-Benoît, Thambo, Caroline, Thumerelle, Renaud, Tournemire (de), Barbara, Tourniaire, Michel, Tsimaratos, François, Varlet, Alain, Verloes, Ariane, Zaloszyc, Catherine, Cyteval, Philippe, Petit, Damien, Bonnard, and Emmanuel, Lescanne
Published: 2020
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16. Auteurs

Author: Antoine, Bourrillon, Grégoire, Benoist, Brigitte, Chabrol, Gérard, Chéron, Emmanuel, Grimprel, Marianne, Alison, Justine, Bacchetta, Alexandre, Belot, Dominique, Brémond-Gignac, Alain, Chantepie, Régis, Coutant, Christophe, Delacourt, Stéphane, Ducassou, Philippe, Duverger, Albert, Faye, Erik, Hervieux, Paul, Jacquin, Pierre-Henri, Jarreau, Thierry, Lamireau, Nicolas, Leboulanger, Joël, Lechevallier, Gérard, Lorette, Stéphanie, Mallet, Gérard, Michel, Yves, Pérel, Sophie, Achard, Alessandro, Amaddeo, Florent, Amatore, Jessica, Amsellem-Jager, Guillaume, Aubertin, Vincent, Audard, Frédérique, Audic, Manon, Bachy, Ananda, Banerjee, Pascal, Barat, Mélisande, Baravalle-Einaudi, Romain, Basmaci, Véronique, Baudouin, Pierre, Bégué, Gérard, Beley, Valérie, Bélien Pallet, Étienne, Bérard, Sophie, Bernard, Isabelle, Bernardini, Patrick, Berquin, Étienne, Bidat, Renaud, Blondé, Nathalie, Bodak, Émilie, Bois, Marie, Bon Saint Côme, Nicolas, Bonnet, Adeline, Boucheron, Bernard, Boudailliez, Natacha, Bouhours Nouet, Claire, Bouvattier, Olivia, Boyer, Étienne, Branchereau, Violaine, Bresson, Guillaume, Bronsard, Apoline, Cailliez, Aline, Cano, Ricardo, Carbajal, Charlotte, Celerier, Hervé, Chambost, Bertrand, Chevallier, Christine, Chiaverini, Isabelle, Claudet, Héloïse, Clerc, Robert, Cohen, François, Corrard, Vincent, Couloigner, Céline, Cudejko, Hélène, De Leersnyder, Renaud, De Tournemire, Dominique, Debray, Chantal, Delafosse, Delphine, Demède, Antoine, Deschildre, Isabelle, Desguerre, Marine, Desjonqueres, Béatrice, Desnous, Chloé, Di Meglio, Jean, Donadieu, Aurélie, Donzeau, Claire, Dossier, Laurence, Dubourg, Jean-Christophe, Dubus, Hubert, Ducou Le Pointe, Véronique, Dufour, Raphaël, Enaud, Brigitte, Fauroux, Marc, Fila, Valérie, Flaum, Daniel, Floret, Pierre, Foucaud, Martine, François, Caroline, Freychet, Marilyn, Fuger, Mathieu, Fusaro, Olivier, Gall, Solène, Ganousse, Joël, Gaudelus, Maxime, Gérard, Muriel, Girard, Thomas, Girard, Christèle, Gras-Le Guen, Lucie, Griffon, Vincent, Guigonis, Myriam, Hazan, Floriane, Hemery, Véronique, Hentgen, Julien, Hogan, Gaëlle, Hubert, Églantine, Hullo, Brice, Ilharreborde, Patrick, Imbert, Béatrice, Jouret, Chantal, Karila, Elsa, Kermorvant, Philippe, Labrune, Marion, Lajus, Anne-Sophie, Lambert, Rémi, Laporte, Élise, Launay, Pierre, Le Coz, Claire, Leblanc, Sophie, Leducq, Bruno, Lefort, Karine, Levieux, Guillaume, Lezmi, Agnès, Linglart, Mathie, Lorrot, Mathilde, Louvigné, Fouad, Madhi, Emmanuel, Mahé, Nausicaa, Malissen, Valérie, Marcou, Christophe, Marguet, Alain, Martinot, Annabel, Maruani, Emmanuel, Mas, Caroline, Maurin, Julie, Mazenq, Anne-Pascale, Michard-Lenoir, Mathieu, Milh, Philippe, Minodier, Florence, Moulin, Olivier, Mouterde, Javotte, Nancy, Valérie, Nouyrigat, Alexandra, Ntorkou, Hayat, Ouaziz, Fabienne, Pangrani, Sophie, Parat, Marine, Parodi, Juliana, Patkai, Géraldine, Patteau, Grégoire, Pech Gourg, Justine, Perrin, Capucine, Picard, Georges, Picherot, Christine, Pietrement, Pierre, Quartier, Béatrice, Quinet, Bruno, Ranchin, Rachel, Reynaud, Estelle, Riblier, Élise, Riquin, Jérémie, Rosain, Sébastien, Rouget, Isabelle, Rouillon, Stéphanie, Rouleau, Caroline, Rousset-Rouvière, Gwenaëlle, Roussey, Catherine, Salinier, Paul, Saultier, Isabelle, Sermet-Gaudelus, Frédéric, Sorge, Nathalie, Soulé, Chantal, Stheneur, Aline, Tamalet, Corentin, Tanné, Maïthé, Tauber, Natacha, Teissier, Briac, Thierry, Guillaume, Thouvenin, Sandra, Timsit, Julie, Toubiana, Michel, Tsimaratos, Dominique, Turck, Diego, Urbina, Amélie, Vadot, de Moulliac Jérôme, Valleteau, Vanessa, Vautier, Sarah, Ventéjou, Raphaël, Vialle, le Sage François, Vié, Nathalie, Villeneuve, Bénédicte, Vrignaud, Isabelle, Vrillon, Armelle, Wastiaux, Ariane, Zaloszyc, and Hyacinthe, Zokou
Published: 2020
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17. Objective videomicroscopy parameters correlate ciliary beating to ultrastructure in primary ciliary dyskinesia

Author: Nathalie Collot, Estelle Escudier, Aline Tamalet, Jean-François Papon, Mathieu Bottier, Guy Montantin, Bruno Louis, Sylvie Tessier, Sylvain Blanchon, and Marie Legendre
Subjects: Pathology, medicine.medical_specialty, cardiovascular system, medicine, Ultrastructure, Inner dynein arm, Outer dynein arm, Biology, Ciliary beating, medicine.disease, Primary ciliary dyskinesia
Abstract: High speed videomicroscopy (HSV) becomes a key test in primary ciliary dyskinesia (PCD), providing a qualitative evaluation and recently a quantitative analysis of ciliary beating. We aimed to correlate ultrastructural phenotype and ciliary beating Method: 75 PCD patients were prospectively included to reach 15 patients per main ultrastructural phenotypes (combined outer/inner dynein arm defect, outer dynein arm defect, inner dynein arm defect with microtubular disorganization, central complex defect and PCD with normal ultrastructure). Ciliary beating was assessed by the proportion of beating ciliated edges, the ciliary beat frequency (CBF), a qualitative evaluation and a quantitative analysis allowing measuring objective parameters Result: Combined outer/inner dynein arm defect induced a total ciliary immotility, whatever the involved gene; (ii) Outer dynein arm defect induced a minimal residual beating with dramatically low CBF related to increased pause and recovery duration, especially in case of DNAI1 mutations; (iii) Inner dynein arm defect induced a weak proportion of ciliated edges still beating, a decreased beating angle and furthermore a relatively conserved CBF in case of CCDC39 mutations; (iv) Central complex defect induced nearly normal quantitative parameters with a circular gyrating motion in a minority of ciliated edges, whatever the involved gene; (v) PCD with normal ultrastructure induced a wide discrepancy in beating parameters but a frequent increased CBF Conclusion: Quantitative analysis by HSV allows objectively detecting abnormal values of ciliary beating parameters characteristic of each of the main ultrastructural phenotypes reported in PCD.
Published: 2016
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18. The development of translated, cross-cultural patient-reported outcome measures for patients with primary ciliary dyskinesia

Author: Aline Tamalet, Jane S. Lucas, Panayiotis Kouis, Lea Heisch, Claudius Werner, Claire O'Neill, Laura Behan, Bridget Contreras, Anika Lofruthe, Guillaume Thouvenin, Konstantinos Giannakou, N.W.P. Rutjes, Christine Edelbusch, Elisabeth Maurer, Helene Kobbernagel, Panayiotis K. Yiallouros, Claudia E. Kuehni, Aristoula Toliopoulou, Tamara Paff, Anu Jose, Maria C. Philipsen, Eric G. Haarman, Audrey Dunn Galvin, and Alexandra L. Quittner
Subjects: medicine.medical_specialty, Pediatrics, business.industry, 030503 health policy & services, Context (language use), language.human_language, German, Danish, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Swiss German Language, Family medicine, Health care, medicine, language, Patient-reported outcome, 030212 general & internal medicine, 0305 other medical science, business, Face validity
Abstract: Introduction: Quality of life is an important parameter in the evaluation of health care and treatments. We have developed the first primary ciliary dyskinesia (PCD) health-related quality of life (HRQoL) measure for children, parents, teenagers and adults (QOL-PCD) in English. Clinical trials on rare diseases like PCD must be conducted in international settings to enrol enough patients, and outcome measures only assess the same thing if translation accounts for the socio-cultural context in which it is understood. This study aims to conduct socio-cultural translations of QOL-PCD into German, Swiss German, Danish, Dutch, French, and Greek. Methodology: We conducted (a) forward translations by 2 independent translators (b) back translation to English of the consensus versions by 1 translator, and (c) cognitive interviews of each age/language version by >5 patients to ensure the “meaning” attributed to each item is similar in different languages and cross-culturally understood. This involved 20 translators, 24 chaired meetings and interviews with 120 patients. Results: Each stage of translation involved comprehensive discussions (>2 hours), resulting in adjustments. 172 items (39-49 items across 4 age groups) were translated averaging 65 working hours per language. Cognitive interviews demonstrated face validity and no missing aspect of HRQoL were identified. International testing additionally provided valuable input on how to proceed for future improvement of QOL-PCD. Conclusion: To meet standards set by international guidelines, this extensive process has produced practical, cross-cultural and equivalent measures for future use as outcome measures in clinical trials.
Published: 2016
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19. Non-invasive CT screening for pulmonary arteriovenous malformations in children with confirmed hereditary hemorrhagic telangiectasia: Results from two pediatric centers

Author: Nurcan, Soysal, Mélanie, Eyries, Suzanne, Verlhac, Virginie, Escabasse, Natascha, Remus, Aline, Tamalet, Jean-Yves, Rioux, Stéphanie, Franchi-Abella, Manuela, Vasile, Sarah, Robert, Céline, Delestrain, Isabelle, Hau, Hubert, Ducou-Le Pointe, Florent, Soubrier, Marie-France, Carette, and Ralph, Epaud
Subjects: Male, Adolescent, Activin Receptors, Type II, Endoglin, Infant, Newborn, Infant, Arteriovenous Malformations, Child, Preschool, Mutation, Humans, Female, Telangiectasia, Hereditary Hemorrhagic, Child, Tomography, X-Ray Computed, Lung
Abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM).to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT).parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast.between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy.This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642-649. © 2017 Wiley Periodicals, Inc.
Published: 2016

20. Long-term effects of azithromycin in patients with cystic fibrosis

Author: Nadia Nathan, Clémentine Samson, Harriet Corvol, Jessica Taytard, Aline Tamalet, Caroline Perisson, Hoang Vu Thien, Annick Clement, Pierre-Yves Boëlle, HAL-UPMC, Gestionnaire, 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), Service de pédiatrie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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), Service de Bactériologie [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biostatistiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], 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), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CHU Saint-Antoine [AP-HP]
Subjects: 0301 basic medicine, Male, Antibiotics, Respiratory System, Azithromycin, medicine.disease_cause, Cystic fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Bacteria resistance, Medicine, Respiratory system, Child, Lung, Children, Respiratory exacerbation, 3. Good health, Anti-Bacterial Agents, Respiratory Function Tests, medicine.anatomical_structure, Staphylococcus aureus, Pseudomonas aeruginosa, Disease Progression, Female, France, Macrolides, medicine.drug, Pulmonary and Respiratory Medicine, medicine.medical_specialty, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Adolescent, medicine.drug_class, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Internal medicine, Drug Resistance, Bacterial, Humans, Pseudomonas Infections, Retrospective Studies, business.industry, Retrospective cohort study, medicine.disease, Lung function, Surgery, 030104 developmental biology, 030228 respiratory system, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract: International audience; BackgroundLow-dose azithromycin has beneficial effects on severity of the lung disease in cystic fibrosis (CF) patients for a period of 6–12 months after initiation of the treatment. Although its impact in the longer term is uncertain, this treatment is frequently used chronically. The aim of this retrospective study was to investigate the effects of low-dose azithromycin treatment on the progression of CF lung disease in patients treated for more than 12 months.MethodsAll of the CF patients followed in our pediatric center and who had been on low-dose azithromycin for more than 12 sequential months were included. The clinical data were collected for one year before and three years after the initiation of the azithromycin treatment. These data comprised lung function analyses, rates of exacerbations and of antibiotic courses, and changes in the airways' bacterial colonization.ResultsA total of 68 patients were included (mean age: 9.95 yrs (3.61)). After 12 months, significant reductions in the numbers of pulmonary exacerbations and antibiotic courses were present. However, this effect was not maintained in the subsequent periods, during which increased rates of both pulmonary exacerbations and antibiotic courses were observed. The lung function decline was not modified during the treatment, and a decreasing time-dependent trend typical of CF was observed for the various parameters. No differences in the airway colonization by pathogens such as P. aeruginosa and methicillin-sensitive and/or -resistant Staphyloccocus aureus were observed during the treatment. However, isolated Staphyloccocus aureus strains became resistant to macrolides after 6 months of azithromycin and remained resistant thereafter.ConclusionsNo clinical benefits of low-doses azithromycin were present after one year of treatment in young CF patients. Selection for macrolide-resistant strains of bacteria occurred, which should lead to a reconsideration of the duration of azithromycin treatment in CF.
Published: 2016
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21. Longitudinal lung function and structural changes in children with primary ciliary dyskinesia

Author: Estelle Escudier, Aline Tamalet, Hubert Ducou Le Pointe, Malika Mahloul, Pierrick Cros, Sylvain Blanchon, Nicole Beydon, Annick Clement, and Marie Lémery Magnin
Subjects: Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Pulmonary function testing, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, 10. No inequality, Prospective cohort study, Primary ciliary dyskinesia, Lung, Bronchiectasis, medicine.diagnostic_test, business.industry, medicine.disease, 3. Good health, Surgery, Peribronchial Thickening, medicine.anatomical_structure, 030228 respiratory system, Pediatrics, Perinatology and Child Health, medicine.symptom, business
Abstract: Background and Objectives Functional and structural lung evaluations are part of the follow-up of patients with primary ciliary dyskinesia (PCD). We aimed to evaluate transversal and longitudinal relationships between lung function test (LFT) and chest computed tomography (CT) in children with PCD, in stable clinical condition. Materials and Methods Data from children followed in the French National Center were retrospectively collected. Inclusion criteria were (i) definitive diagnosis of PCD, (ii) age less than 15 years at the beginning of follow-up, (iii) at least 8 years of follow-up, (iv) at least two couples of concurrent CT and LFT available in a phase of clinical stability of the lung disease without modification of the treatment regimen in the last 4 weeks. Twenty children (median age at entry 4.6 years, median follow-up 15.4 years) were included. Concurrent LFT (blood gas and spirometry) and CT (score) results were recorded. Results LFT indices (PaO2 (n = 210), FVC, FEV1, FEF2575% (n = 195)) significantly decreased with age, and the mean annual decrease (z-score (% predicted)) was −0.17 (−0.49%), −0.09 (−0.50%), −0.10 (−0.89%), and −0.07 (−1.73%), respectively. First CT (median age 8.7 years) revealed bronchiectasis (70%), mucous plugging (70%), peribronchial thickening (90%), parenchymal abnormalities (65%), and hyperinflation (50%). CT scores (n = 74) significantly increased with age, and was negatively correlated to PaO2, FVC, FEV1, and FEF2575% longitudinal changes. Conclusion In stable clinical condition, functional, and structural progressive impairments significantly correlated in children with PCD. Further prospective studies, including large populations of patients with various levels of disease severity, are needed to confirm whether lung function follow-up can be used to adjust CT frequency and help at minimizing the radiation burden in children with a good life expectancy. Pediatr Pulmonol. 2012. 47:816–825. © 2012 Wiley Periodicals, Inc.
Published: 2012
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22. Influenza-Like Illness Responsible for Severe Exacerbations in Asthmatic Children During H1N1 Pandemic: A Survey Before Vaccination

Author: Valentine Marchac, Jean-Luc Iniguez, Bruno Mahut, Guillaume Aubertin, Christophe Delclaux, Corinne Troadec, Marie-Noëlle Lebras, L. Réfabert, Gilles Chatellier, and Aline Tamalet
Subjects: Male, Pulmonary and Respiratory Medicine, Paris, Pediatrics, medicine.medical_specialty, Exacerbation, Influenza A Virus, H1N1 Subtype, Adrenal Cortex Hormones, Surveys and Questionnaires, Influenza, Human, Pandemic, medicine, Sore throat, Humans, Immunology and Allergy, Longitudinal Studies, Child, Pandemics, Asthma, Influenza-like illness, business.industry, Vaccination, virus diseases, medicine.disease, Suburban Population, respiratory tract diseases, Hospitalization, H1n1 pandemic, Asthmatic children, Influenza Vaccines, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, medicine.symptom, business
Abstract: Asthma seems to be the more prevalent underlying condition in patients hospitalized for H1N1-related flu.A prospective survey was conducted during the early phase of H1N1 pandemic in France in asthmatic children before vaccination to assess whether severe exacerbations in childhood asthma are associated with influenza-like illness (ILI, the definition of H1N1-related flu in a pandemic). Eight pediatricians in primary care distributed in three localities (Paris, south suburb, and west suburb) conducted the survey (4 weeks/locality from week 36 to 47). At each visit, the pediatrician filled a questionnaire entering the information regarding asthma treatment, severe exacerbation (at least 3 days' use of systemic corticosteroids), and ILI (temperature ≥37.8°C, cough, and/or sore throat, in the absence of a known cause other than influenza) during the past 3 weeks.The survey included 1155 asthmatic children (mean age [SD]: 7.5 years [4.1]); almost all visits were scheduled (99%). A severe exacerbation was recorded in 121 children [10.5%; 95% confidence interval (CI): 8.7-12.2%], which was concomitant with ILI in 20 children (16.5%; 95% CI: 9.9-23.2%), whereas 1034 children did not exhibit any exacerbation. In these latter children, 40 ILI were observed (3.9%; 95% CI: 2.7-5.0%), which constituted a significantly lesser percentage as compared with children with both exacerbation and ILI (p.0001). This result remained significant in each locality. Overall, 60/1155 (5.2%; 95% CI: 3.9-6.5%) asthmatic children had an ILI.Our survey shows that severe exacerbation and ILI are strongly associated during the H1N1 pandemic in asthmatic children.
Published: 2011
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23. Gaz exchange, nasal nitric oxyde levels and lung function tests in children with primary ciliary dyskinesia

Author: Annick Clement, Aline Tamalet, Nicole Beydon, Estelle Escudier, Guillaume Thouvenin, and Harriet Corvol
Subjects: Univariate analysis, medicine.medical_specialty, Pediatrics, Lung, business.industry, medicine.disease, Gastroenterology, Nitric oxide, Hypoxemia, Pulmonary function testing, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Internal medicine, Ear lobe, otorhinolaryngologic diseases, medicine, medicine.symptom, business, Lung function, Primary ciliary dyskinesia
Abstract: Introduction: Capillary partial pressure of O 2 (PcapO 2 ) was found to decrease with age in children with primary ciliary dyskinesia (PCD) while PcapCO 2 remained steady. Objectives: To further explore the relationship between PcapO 2 , nasal Nitric Oxide (nNO) output and lung function (LF) in children with PCD. Patients and methods: Retrospective monocentric study in children referred to our national paediatric reference center for rare lung diseases for PCD diagnostic work-up, and in whom ear lobe capillary blood gas was available along with nNO and/or LF measurements. Results: 30 PCD children were included (18 girls, median age 11.5 (0.7 to 18.2) years). Median PcapO 2 was -1.9 (-5.2 to 2.2) z-score, median nNO in 27 children was 61 (20.3 to 697) ppb and median FEV 1 in 24 children was -2 (-4.7 to 2.18) z-score. In univariate analysis, there was a significant relationship between PcapO 2 and nNO, age, and LF indices (see table). In multivariate analysis, there was a significant relationship between PcapO 2 and nNO (p=0.02), and FEF 75% (p Conclusion: In the study children, low PcapO 2 was correlated with decrease nNO output and one LF indice. This could explain the early occurrence of hypoxemia in the course of PCD disease.
Published: 2015
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24. RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

Author: André Coste, Aline Tamalet, Esther Kott, Bruno Copin, Jacques Cadranel, Philippe Duquesnoy, Harriet Corvol, Anissa Souayah, Ludovic Jeanson, Jean Francois Papon, Marie Legendre, Jacques de Blic, Guy Montantin, Bruno Louis, Estelle Escudier, Nathalie Collot, Annick Clement, Julie Désir, Serge Amselem, Sylvie Tissier, Florence Dastot-Le Moal, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique et embryologie médicales [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 Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], 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)-CHU Trousseau [APHP], Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), 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), and Sorbonne Université - Faculté de Médecine (SU FM)
Subjects: Axoneme, [SDV]Life Sciences [q-bio], Nerve Tissue Proteins, Flagellum, Biology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Radial spoke, Report, Genetics, medicine, Humans, Genetics(clinical), Genetic Predisposition to Disease, Cilia, Gene, Genetics (clinical), Primary ciliary dyskinesia, Microscopy, Video, Kartagener Syndrome, Cilium, medicine.disease, Phenotype, Cell biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Motile cilium
Abstract: International audience; Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive condition resulting from structural and/or functional defects of the axoneme in motile cilia and sperm flagella. The great majority of mutations identified so far involve genes whose defects result in dynein-arm anomalies. By contrast, PCD due to CC/RS defects (those in the central complex [CC] and radial spokes [RSs]), which mightbe difficult to diagnose, remains mostly unexplained. We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects. RSPH3, whose ortholog in the flagellated alga Chlamydomonas reinhardtii encodes a RS-stalk protein, is mainly expressed in respiratory and testicular cells. Its protein product, which localizes within the cilia of respiratory epithelial cells, was undetectable in airway cells from an individual with RSPH3 mutations and in whom RSPH23 (a RS-neck protein) and RSPH1 and RSPH4A (RS-head proteins) were found to be still present within cilia. In the case of RSPH3 mutations, high-speed-videomicroscopy analyses revealedthe coexistence of immotile cilia and motile cilia with movements of reduced amplitude. A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects. Overall, this study shows that RSPH3 mutations contribute to disease in more than 10% of PCD-affected individualswith CC/RS defects, thereby allowing an accurate diagnosis to be made in such cases. It also unveils the key role of RSPH3 in the proper building of RSs and the CC in humans.
Published: 2015
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25. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa

Author: Maciej Geremek, B. Pelosse, Annick Clement, Estelle Escudier, Aline Tamalet, Michał Witt, Gilles Roger, Bénédicte Duriez, Anne-Marie Bridoux, Sandrine Marlin, Serge Amselem, Anne Moore, Bertrand Delaisi, and André Coste
Subjects: Adult, Male, Adolescent, Genotype, DNA Mutational Analysis, Dynein, Respiratory Mucosa, Biology, Autosomal recessive trait, Retinitis pigmentosa, otorhinolaryngologic diseases, Genetics, medicine, Humans, Cilia, Eye Proteins, Genetics (clinical), X chromosome, Primary ciliary dyskinesia, Kartagener Syndrome, Cilium, Genetic Diseases, X-Linked, Retinitis pigmentosa GTPase regulator, medicine.disease, Phenotype, Pedigree, Mutation, Original Article, Female, Retinitis Pigmentosa, Microsatellite Repeats
Abstract: Introduction: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. Results: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene ( RPGR ) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. Conclusion: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.
Published: 2005
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26. Carcinoid and mucoepidermoid bronchial tumours in children

Author: Hubert Ducou Le Pointe, Liliane Boccon-Gibod, M. Larroquet, Brigitte Fauroux, Aline Tamalet, Annick Clement, and Valérie Aynie
Subjects: Male, Thorax, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Carcinoid Tumor, Pneumonectomy, Mucoepidermoid carcinoma, Biopsy, medicine, Carcinoma, Humans, Carcinoid tumour, Child, Retrospective Studies, medicine.diagnostic_test, business.industry, Bronchial Neoplasms, Prognosis, medicine.disease, Surgery, Radiation therapy, Treatment Outcome, Cardiothoracic surgery, Pediatrics, Perinatology and Child Health, Carcinoma, Mucoepidermoid, Female, France, business
Abstract: The aim of the study was to determine the characteristic features and outcome of carcinoid or mucoepidermoid tumours in children. A retrospective analysis of all patients treated for a carcinoid or mucoepidermoid tumour in France between 1984 and 2001 was performed. There were 11 cases of carcinoid tumour and 6 cases of mucoepidermoid tumour. The mean age of the patients was 10.5±3.0 years, with a range of 5 to 15 years. Twelve and 6 patients presented with evidence of bronchial obstruction and haemoptysis, respectively. Fibre optic bronchoscopy confirmed the presence of a bronchial tumour in all cases and endobronchial biopsies were diagnostic in 11 of 12 cases. A chest CT scan revealed the presence of a hypervascular tumour in 8 of 12 patients. The distribution of the location of the tumours was equal between the right and the left lung, and, in 9 cases, the airways were totally occluded by the tumour. Complete surgical resection (lobectomy in 15 patients and pneumonectomy in 2 patients) was performed in all cases without pre-operative chemotherapy or radiotherapy. The mean duration of follow-up was 4.0±3.0 years. In 2 patients, auscultation assymetry and an episode of haemoptysis revealed the recurrence of a mucoepidermoid tumour, successfully cured by removal of the tumour and chemotherapy and radiotherapy in one child. No death was observed. Conclusion:Pulmonary carcinoid and mucoepidermoid tumours are rare in children. Bronchoscopic removal should not be performed. With aggressive surgical therapy, the prognosis is excellent. Fibre optic bronchoscopy confirms the presence of an endobronchial mass. A biopsy is needed for diagnosis and complete surgical removal is the treatment of choice. Long-term results are excellent but a clinical follow-up is recommended.
Published: 2005
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27. L’analyse quantitative du mouvement ciliaire permet d’identifier le phénotype ultra-structural des dyskinésies ciliaires primitives

Author: Florence Dastot, Catherine Faucon, André Coste, S. Tissier, Mathieu Bottier, Serge Amselem, J.-F. Papon, Bruno Copin, Annick Clement, Marie Legendre, Guy Montantin, Sylvain Blanchon, Aline Tamalet, Estelle Escudier, Nathalie Collot, and Bruno Louis
Subjects: Pulmonary and Respiratory Medicine
Abstract: Introduction Les dyskinesies ciliaires primitives (DCP) sont un groupe de maladies genetiques rares responsable d’une anomalie du mouvement des cils respiratoires. Le diagnostic est classiquement confirme grâce a l’identification d’une anomalie de l’ultra-structure ciliaire par microscopie electronique a transmission. L’analyse genetique ne peut etre proposee en premiere intention, etant donne le nombre (> 30 genes) et la taille (> 80 exons) des genes impliques. Nous avons souhaite etudier si la mesure objective du mouvement ciliaire par video-microscopie a haute vitesse pourrait predire le phenotype ultra-structural et ainsi guider l’analyse genetique. Methodes Nous avons prospectivement inclus 75 patients ayant un diagnostic certain de DCP, presentant un des 5 principaux phenotypes ultra-structuraux identifie par microscopie electronique (15 patients par groupe), et pour lesquels tous les genes correspondants ont ete sequences. L’etude du mouvement ciliaire a inclus le pourcentage de cil battant, la frequence de battement ciliaire, une evaluation qualitative et la mesure quantitative de 12 parametres du mouvement ciliaire. Resultats L’absence combinee des bras de dyneine externe et interne induit une immobilite ciliaire totale, quel que soit le gene implique. L’absence de bras de dyneine externe permet un rare mouvement ciliaire residuel avec une frequence de battement effondre en rapport avec un allongement du temps de pause, notamment en cas de mutation de DNAH1. L’absence de bras de dyneine interne avec desorganisation axonemale induit un faible pourcentage de cil battant avec une diminution de l’angle de battement, associe en cas de mutation de CCDC39 a une frequence maximale de battement augmentee. L’absence de complexe central permet un mouvement ciliaire relativement conserve, malgre une minorite de cil presentant un mouvement ciliaire circulaire, quel que soit le gene implique. Dans les DCP avec ultra-structure normale, les parametres de mouvement ciliaires ont des valeurs particulierement heterogenes, malgre une frequence de battement ciliaire augmentee avec une frequence maximale extreme. Conclusion L’analyse quantitative du mouvement ciliaire par video-microscopie a haute vitesse permet l’identification de parametres objectifs caracteristiques du phenotype ultra-structural des DCP.
Published: 2017
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28. Chronic interstitial lung disease in children: Response to high-dose intravenous methylprednisolone pulses

Author: Annick Clement, Aline Tamalet, Guy Tournier, Brigitte Fauroux, Pascale Desmarquest, M. Boule, and Liliane Boccon-Gibod
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Adolescent, medicine.drug_class, Biopsy, Anti-Inflammatory Agents, Methylprednisolone, Hypoxemia, Idiopathic pulmonary fibrosis, Prednisone, Bronchoscopy, medicine, Humans, Prospective Studies, Lung, Dose-Response Relationship, Drug, Respiratory distress, business.industry, Interstitial lung disease, Infant, medicine.disease, Surgery, Treatment Outcome, Child, Preschool, Anesthesia, Chronic Disease, Injections, Intravenous, Pediatrics, Perinatology and Child Health, Prednisolone, Drug Evaluation, Corticosteroid, Female, medicine.symptom, Lung Diseases, Interstitial, business, Bronchoalveolar Lavage Fluid, medicine.drug
Abstract: The prognosis for children with chronic interstitial lung disease is poor and the mortality rate is high, especially in infants. This explains the many therapeutical protocols which have been proposed and investigated by several authors. In the present work, we evaluated the response of three infants with idiopathic pulmonary fibrosis to high-dose intravenous prednisolone pulses. The patients were referred to the department at the age of 4, 17, and 3 months, respectively. The diagnosis was confirmed by open lung biopsy and intravenous pulse methyl prednisolone therapy was started with the following protocol: 300 mg/m2 methylprednisolone daily for 3 days, repeated every 4 to 6 weeks. Because of the extreme severity of the respiratory distress at the time of diagnosis, the intravenous pulse treatments were initially complemented by oral prednisone. Clinical improvement was noticed within 6 months with progressive correction of hypoxemia. After follow-up for 3.5 to 4 years, with a total number of pulses of 37, 26, and 32, respectively, the children are symptom-free and do not require oxygen supplementation. During this period, no side effects and no adrenal insufficiency could be documented. Based on current knowledge of steroid action, it can be speculated that the response to intermittent high-dose intravenous methylprednisolone may explain the ability of this mode of hormone administration to maintain an adequate level of glucocorticoid receptor expression. More information and trials through multicenter collaborations are needed to assess therapeutical protocols of repeated high-dose intravenous steroid treatment.
Published: 1998
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29. Primary ciliary dyskinesia presentation in 60 children according to ciliary ultrastructure

Author: Serge Amselem, Brigitte Fauroux, Nicole Beydon, Aline Tamalet, Christelle Vallet, Michèle Boulé, Annick Clement, Estelle Escudier, Sylvain Blanchon, Anne Marie Vojtek, Françoise Roudot-Thoraval, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Mucoviscidose et bronchopathies chroniques : biopathologie et phénotype cliniques - Cystic Fibrosis and Bronchial Diseases, Institut Pasteur [Paris] (IP)-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)-Université Paris Cité (UPCité), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHI Créteil, Legs Poix from the Chancellerie des UniversitesAssistance Publique-Hopitaux de Paris : PHRC AOM06053 et P060245Milena Carvajal ProKartagener FoundationFondation pour la Recherche Medicale : DEQ20120323689, Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], 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)-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), Service de génétique et embryologie médicales [CHU Trousseau], Service d'explorations fonctionnelles [CHU Trousseau], and Couvet, Sandrine
Subjects: Male, medicine.medical_specialty, Pathology, Adolescent, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Statistics, Nonparametric, Pulmonary function testing, Internal medicine, medicine, Electron microscopy, Humans, Cilia, Child, Respiratory Tract Infections, Primary ciliary dyskinesia, Retrospective Studies, Ciliary beat frequency Dynein Electron microscopy Kartagener syndrome Pulmonary function test, [SDV.GEN]Life Sciences [q-bio]/Genetics, Respiratory tract infections, business.industry, Kartagener Syndrome, Cilium, Respiratory disease, Ciliary beat frequency, Dynein, Pulmonary function test, Dyneins, medicine.disease, Bronchiectasis, Respiratory Function Tests, [SDV] Life Sciences [q-bio], Situs inversus, Microscopy, Electron, Otitis, Spirometry, Child, Preschool, Pediatrics, Perinatology and Child Health, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, medicine.symptom, business, Tomography, X-Ray Computed
Abstract: International audience; Primary ciliary dyskinesia (PCD) is an inherited disease related to ciliary dysfunction, with heterogeneity in clinical presentation and in ciliary ultrastructural defect. Our study intended to determine if there are phenotypic differences in patients with PCD based on ciliary ultrastructural abnormality. In this retrospective study carried out among 60 children with a definitive diagnosis of PCD, we analyzed clinical, radiological, and functional features at diagnosis and at last recorded visit, according to cilia defect (absence of dynein arms: DAD group, n = 36; abnormalities of the central complex: CCA group, n = 24). Onset of respiratory symptoms occurred later in the CCA than in the DAD group (9.5 versus 0.5 months, p = 0.03). Situs inversus was only observed in the DAD group, while respiratory disease in siblings were more frequent in the CCA group (p = 0.003). At diagnosis, clinical presentation was more severe in the CCA group: frequency of respiratory tract infections (p = 0.008), rhinosinusitis (p = 0.02), otitis complications (p = 0.0001), bilateral bronchiectasis (p = 0.04), and number of hypoxemic patients (p = 0.03). Pulmonary function remained stable in both groups, but outcome was better in the CCA than in the DAD group: less antibiotic therapy and hypoxemic patients (p = 0.004). In conclusion, our results underlined the relationship between the severity of clinical presentation and the ultrastructural ciliary defect.
Published: 2012
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30. Diagnostic algorithm for Primary Ciliary Dyskinesia: recommendations of the French National Centre for Rare Respiratory Diseases

Author: Aline Tamalet, Jean-François Papon, Sylvain Blanchon, Nicole Beydon, Annick Clement, Estelle Escudier, and L. Bassinet
Subjects: Infertility, medicine.medical_specialty, Poster Presentation, otorhinolaryngologic diseases, medicine, Practical algorithm, Cell Biology, Disease, Biology, medicine.disease, Intensive care medicine, Bioinformatics, Primary ciliary dyskinesia
Abstract: Background Primary Ciliary Dyskinesia (PCD) is a inherited disorder characterized by abnormal ciliary structure/function, responsible for impaired muco-ciliary transport and infertility. The diagnosis is often delayed for several years though PCD is a rare (~1/20,000) and heterogeneous disease. We elaborated recommendations aiming at improving the quality and efficacy of PCD diagnosis. Methods A multicentric working group, created in 2009 within the French National Centre for Rare Respiratory Diseases, elaborated precise and practical algorithm for PCD diagnosis, based on their experience and the recent literature. It includes adults and paediatric physicians, biologists and technicians involved in PCD, dealing since many years with the difficulties to confirm this diagnosis.
Published: 2012
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31. Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia

Author: Sylvain Blanchon, Marie Legendre, Bruno Copin, Philippe Duquesnoy, Guy Montantin, Esther Kott, Florence Dastot, Ludovic Jeanson, Marine Cachanado, Alexandra Rousseau, Jean François Papon, Nicole Beydon, Jacques Brouard, Bruno Crestani, Antoine Deschildre, Julie Désir, Hélène Dollfus, Bruno Leheup, Aline Tamalet, Caroline Thumerelle, Anne-Marie Vojtek, Denise Escalier, André Coste, Jacques de Blic, Annick Clément, Estelle Escudier, Serge Amselem, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique et embryologie médicales [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), Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], 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)-CHU Trousseau [APHP], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'ORL [Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), Service d'explorations fonctionnelles [CHU Trousseau], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CIC Hôpital Bichat, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, CHU Lille, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Erasme [Bruxelles], Université libre de Bruxelles (ULB), CHU Strasbourg, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Intercommunal de Cornouaille (CHIC), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Assistance Publique-Hopitaux de Paris (PHRC AOM06053, P060245), the Fondation pour la Recherche Medicale, the Legs Poix from the Chancellerie des Universites, and the MilenaCarvajald ProKartagener Foundation., and Couvet, Sandrine
Subjects: Adult, Male, Axoneme, Adolescent, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Statistics, Nonparametric, Cohort Studies, Genetics, Humans, Cilia, Child, Genetics (clinical), Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kartagener Syndrome, Infant, Proteins, Middle Aged, [SDV] Life Sciences [q-bio], Cytoskeletal Proteins, Phenotype, Child, Preschool, Mutation, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female
Abstract: International audience; Background: CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described.Methods: All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella.Results: Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones.Conclusions: CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.
Published: 2012
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32. Loss-of-Function Mutations in LRRC6 , a Gene Essential for Proper Axonemal Assembly of Inner and Outer Dynein Arms, Cause Primary Ciliary Dyskinesia

Author: Philippe Duquesnoy, Estelle Escudier, Jean-François Papon, Jean-Pierre Siffroi, Florence Dastot-Le Moal, Annick Clement, Nathalie Rives, Aline Tamalet, Guy Montantin, André Coste, Serge Amselem, Esther Kott, Denise Escalier, Marie Legendre, Aminata Touré, Jacques de Blic, Valérie Mitchell, Bruno Copin, Ludovic Jeanson, Couvet, Sandrine, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique et embryologie médicales [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), Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], 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)-CHU Trousseau [APHP], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, CHI Créteil, CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Axoneme, [SDV]Life Sciences [q-bio], Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, Flagellum, Biology, medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Frameshift mutation, Consanguinity, Intraflagellar transport, Report, Consensus Sequence, Gene Order, Genetics, medicine, Humans, Genetics(clinical), Amino Acid Sequence, Cilia, Alleles, Genetics (clinical), Primary ciliary dyskinesia, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kartagener Syndrome, Cilium, Proteins, Axonemal Dyneins, medicine.disease, Phenotype, [SDV] Life Sciences [q-bio], Cytoskeletal Proteins, Protein Transport, Fertility, Sperm Tail, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, Sequence Alignment
Abstract: International audience; Primary ciliary dyskinesia (PCD) is a group of autosomal-recessive disorders resulting from cilia and sperm-flagella defects, which lead to respiratory infections and male infertility. Most implicated genes encode structural proteins that participate in the composition of axonemal components, such as dynein arms (DAs), that are essential for ciliary and flagellar movements; they explain the pathology in fewer than half of the affected individuals. We undertook this study to further understand the pathogenesis of PCD due to the absence of both DAs. We identified, via homozygosity mapping, an early frameshift in LRRC6, a gene that encodes a leucine-rich-repeat (LRR)-containing protein. Subsequent analyses of this gene mainly expressed in testis and respiratory cells identified biallelic mutations in several independent individuals. The situs inversus observed in two of them supports a key role for LRRC6 in embryonic nodal cilia. Study of native LRRC6 in airway epithelial cells revealed that it localizes to the cytoplasm and within cilia, whereas it is absent from cells with loss-of-function mutations, in which DA protein markers are also missing. These results are consistent with the transmission-electron-microscopy data showing the absence of both DAs in cilia or flagella from individuals with LRRC6 mutations. In spite of structural and functional similarities between LRRC6 and DNAAF1, another LRR-containing protein involved in the same PCD phenotype, the two proteins are not redundant. The evolutionarily conserved LRRC6, therefore, emerges as an additional player in DA assembly, a process that is essential for proper axoneme building and that appears to be much more complex than was previously thought.
Published: 2012
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33. Clinical changes of patients with cystic fibrosis during transition from pediatric to adult care

Author: Dominique Hubert, Isabelle Sermet-Gaudelus, Aline Tamalet, N. Desmazes-Dufeu, Muriel Le Bourgeois, Ingrid Duguépéroux, and M. Gerardin
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Pancreatic disease, Adolescent, Cystic Fibrosis, Cystic fibrosis, Pulmonary function testing, Adolescent medicine, Young Adult, Adolescent Medicine, medicine, Internal Medicine, Humans, Young adult, Practice Patterns, Physicians', Lung, Retrospective Studies, business.industry, Respiratory disease, Public Health, Environmental and Occupational Health, Retrospective cohort study, medicine.disease, Anti-Bacterial Agents, Psychiatry and Mental health, Pediatrics, Perinatology and Child Health, Disease Progression, Female, business, Body mass index
Abstract: To evaluate the clinical changes of adults with cystic fibrosis (CF) during transition from a pediatric to adult CF center.Data were collected at the time of transfer, 1 year earlier and 1 year later, for all patients in our adult CF center arriving from one of the three pediatric CF centers in Paris between January 2001 and June 2004.Sixty-three of the 68 patients (transferred at a median age of 21.0 years) were regularly attending this adult CF center after 1 year and one had died. The mean number of outpatient visits increased in the year after transfer (5.7 vs. 3.8 in the year before, p.001). The occurrence of clinical events and the rate of bronchial colonization did not change. Pseudomonas aeruginosa was found in about 60% of patients at any time. Pulmonary function declined regularly with no statistically significant difference in the rate of decline between the 2 years of follow-up (FEV 1 was 54.7% predicted at transfer). Nutritional status remained stable (mean body mass index was 19.1 kg/m2). The number and duration of oral and i.v. antibiotic courses did not change, but more patients received them at home (p.001) and self-administered physiotherapy after transfer (p = .001). The proportion of students decreased from 79.3% to 48.1% (p = .02) and the proportion in the workforce increased from 12.7% to 20.4% after transfer.Patients with CF remained clinically stable during transition and progressively acquired autonomy.
Published: 2007

34. [Protein repair therapy in cystic fibrosis]

Author: Annick, Clément, Aline, Tamalet, Brigitte, Fauroux, and Ralph, Epaud
Subjects: Cystic Fibrosis, Mutation, Cystic Fibrosis Transmembrane Conductance Regulator, Gene Expression, Humans, Genetic Therapy
Abstract: In the past few years since the cloning of the gene defective in cystic fibrosis, much has been learned on the function of the protein cystic fibrosis transmembrane conductance regulator (CFTR) and on the mechanisms regulating its expression. Based on the current understanding of the processes involved in lung disease progression, a number of approaches have been developed using not only gene therapy, but also pharmacological agents. Several of these agents have been reported to restore function to CFTR with specific mutations.
Published: 2003

35. Otologic Features in Children With Primary Ciliary Dyskinesia

Author: Erea-Noel Garabedian, Brigitte Fauroux, Pierre Chauvin, Estelle Escudier, André Coste, Gilles Roger, Aline Tamalet, and Virginie Prulière-Escabasse
Subjects: Male, medicine.medical_specialty, Adolescent, Hearing loss, macromolecular substances, Article, 03 medical and health sciences, 0302 clinical medicine, Audiometry, otorhinolaryngologic diseases, medicine, Humans, Young adult, Child, Hearing Loss, 030223 otorhinolaryngology, Grommet, Retrospective Studies, Primary ciliary dyskinesia, Chi-Square Distribution, medicine.diagnostic_test, Kartagener Syndrome, business.industry, Infant, General Medicine, medicine.disease, Anti-Bacterial Agents, Bronchiectasis, Conductive hearing loss, Surgery, Otitis Media, medicine.anatomical_structure, 030228 respiratory system, Otorhinolaryngology, Child, Preschool, Middle ear, Ciliary Motility Disorders, Female, sense organs, medicine.symptom, business
Abstract: To analyze otologic features in patients with primary ciliary dyskinesia (PCD) aged 0 to 18 years and to evaluate the correlation between ultrastructural defects and severity of otologic features.Retrospective study.Pediatric referral center.Fifty-eight patients with PCD were evaluated in the following 4 age intervals: group 1, preschool (≤ 5 years [n = 47]); group 2, school (6-11 years [n = 50]); group 3, teenagers (12-17 years [n = 34]); and group 4, young adults (≥ 18 years; 27 years for the oldest [n = 10]). Follow-up was 2 to 6 years in each age group; 26 patients had total follow-up of more than 12 years. Ultrastructural defects occurred in the outer dynein arm (n = 33), the inner dynein arm (n = 13), and the central complex (n = 11). One patient had typical Kartagener syndrome with typical PCD features but normal ciliary ultrastructure.Frequency of acute otitis media, otitis media with effusion, otorrhea, chronic otitis media, hearing loss, and middle ear surgery and type of antibiotic regimen according to age and type of defect.Recurrent acute otitis media decreased from group 1 (32 of 47 [68%]) to group 4 (0 of 10 [0%]) (P.001). Otitis media with effusion was more severe in groups 1 through 3 than in group 4 (P = .02). Otorrhea decreased in group 4: 30% vs 80% (3 of 10 vs 36 of 41) in the other groups (P.001). Half of the patients with tympanostomy tubes eventually had tympanic perforation. Hearing loss was moderate in groups 1 through 3 and mild in group 4. Continuous antibiotic therapy could be slightly reduced only in group 4. Central complex defect was a significant marker of severity for all these criteria.Despite continuous antibiotic therapy, the middle ear condition in PCD remained severe throughout childhood, with improvement only after age 18 years. Armstrong grommet placement did not improve the middle ear condition. Central complex defect is a marker of severity.
Published: 2010
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36. Azithromycin long term effects in children with cystic fibrosis

Author: A. Lemaire, J.-F. Vibert, Delphine Michon, Harriet Corvol, Aline Tamalet, Annick Clement, A. Blondel, Malika Mahloul, Delphine Feldmann, and Brigitte Fauroux
Subjects: Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, medicine, Pediatrics, Perinatology, and Child Health, Azithromycin, business, medicine.disease, Cystic fibrosis, medicine.drug, Term (time)
Published: 2009
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37. 078 Évaluation de la fréquence des anomalies fonctionnelles respiratoires avant l’âge de 1 an chez le nourrisson atteint de mucoviscidose

Author: Michèle Boulé, Annick Clement, L. Sandu-Maingot, Aline Tamalet, M.C. La Rocca, and Brigitte Fauroux
Subjects: Pulmonary and Respiratory Medicine
Published: 2007
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38. Abnormal Central Complex Is a Marker of Severity in the Presence of Partial Ciliary Defect

Author: T.{s. A. Baculard, Estelle Escudier, Michèle Boulé, F. Roudot-Thoraval, Aline Tamalet, Gilles Roger, P. Desmarquest, M. C. Millepied, and Annick Clement
Subjects: Male, Chronic bronchitis, Pathology, medicine.medical_specialty, Adolescent, Biopsy, Population, Bronchi, Pulmonary function testing, medicine, Humans, Cilia, Bronchitis, Child, education, Respiratory Tract Infections, Primary ciliary dyskinesia, education.field_of_study, Bronchiectasis, Respiratory tract infections, business.industry, Cilium, Infant, medicine.disease, Situs inversus, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business, Ciliary Motility Disorders, Follow-Up Studies
Abstract: Background. Ciliary ultrastructural defects with total lack of dynein arms (DA) cause abnormal mucociliary function leading to the chronic infections observed in primary ciliary dyskinesia. The role of partial ciliary ultrastructural defects, especially those involving the central complex, and their relationship with respiratory symptoms have been less thoroughly investigated. Objective. In a pediatric population with partial ciliary defects, we determined the relationship(s) between ultrastructural findings, ciliary motility, and clinical and functional features, and evaluated the outcome of this population. Design. We analyzed the clinical presentation and pulmonary function of 43 children with chronic bronchitis and partial ultrastructural defects (from 15% to 90%) of their respiratory cilia demonstrated on bronchial biopsies. The study population was divided into 3 groups according to ciliary ultrastructure: the main ultrastructural defect concerned the central complex in 23 patients (CC group), peripheral microtubules in 8 patients (PMT group), and DA in 12 patients (DA group). Results. The percentage of ciliary defects was lower in the PMT group than in the CC and DA groups. Patients in the PMT group had less severe disease with frequent normal ciliary motility. Patients in the CC group had initially a higher incidence of respiratory tract infections, extensive bronchiectasis frequently requiring surgery, and arguments in favor of a congenital origin (high proportion of sibling form). Partial absence of DA, although of congenital origin, was associated with a good prognosis. In all groups, follow-up showed that the functional prognosis remained good with appropriate treatment. Conclusions. In children with chronic respiratory infections, presence of situs inversus, sibling form, obstructive pulmonary syndrome, or bronchiectasis required ultrastructural analysis, regardless of ciliary motility. Detection of CC abnormalities is a marker of severity and required intensive therapy and close follow-up.
Published: 2001
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39. Longitudinal lung function and structural changes in children with primary ciliary dyskinesia

Author: Annick Clement, Nicole Beydon, M Lémery Magnin, Malika Mahloul, Aline Tamalet, Estelle Escudier, H. Ducou Le Pointe, Pierrick Cros, Sylvain Blanchon, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [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), 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), Service de Pneumologie pédiatrique [CHU Trousseau], and BMC, Ed.
Subjects: 0303 health sciences, lcsh:Cytology, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Bioinformatics, medicine.disease, Molecular medicine, Human genetics, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Poster Presentation, medicine, lcsh:QH573-671, Receptor, Developmental biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030217 neurology & neurosurgery, Lung function, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Primary ciliary dyskinesia
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