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1. Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial

Author

Katrina M. Pollock, Hannah M. Cheeseman, Alexander J. Szubert, Vincenzo Libri, Marta Boffito, David Owen, Henry Bern, Leon R. McFarlane, Jessica O'Hara, Nana-Marie Lemm, Paul McKay, Tommy Rampling, Yee Ting N. Yim, Ana Milinkovic, Cherry Kingsley, Tom Cole, Susanne Fagerbrink, Marites Aban, Maniola Tanaka, Savviz Mehdipour, Alexander Robbins, William Budd, Saul Faust, Hana Hassanin, Catherine A. Cosgrove, Alan Winston, Sarah Fidler, David Dunn, Sheena McCormack, Robin J. Shattock, Kirsty Adams, Fahimah Amini, Nafisah B Atako, Amalina Bakri, Wendy Barclay, Elizabeth Brodnicki, Jonathan C Brown, Ruth Byrne, Rowena Chilvers, Sofia Coelho, Suzanne Day, Monica Desai, Eleanor Dorman, Tamara Elliott, Katie E Flight, James Fletcher, John Galang, Jagruti Gohil, Aneta Gupta, Chris Harlow, Kai Hu, Mohini Kalyan, Dominic Lagrue, Ely Liscano, Cecilia Njenga, Krunal Polra, Derecia A Powlette, Paul Randell, Mary Rauchenberger, Ianto Redknap, Maravic Ricamara, Paul Rogers, Hadijatou Sallah, Karnyart Samnuan, Michael Schumacher, Zareena Shah, Rachel Shaw, Thomas Shaw, Stefan Sivapatham, Susie Slater, Kim Sorley, Regina Storch, Elizabeth Tan, Tricia Tan, Lieze Thielemans, Sarah Whitely, Charlotte Valentine, Jeeva Varghese, Asha Vikraman, Martin Wilkins, The Sir Joseph Hotung Charitable Settlement, and National Institute for Health Research

Subjects
NSP, non-structural protein, medicine.medical_specialty, Medicine (General), Coronavirus disease 2019 (COVID-19), Article, AEs, adverse events, R5-920, Internal medicine, Medicine, Seroconversion, Adverse effect, biology, LNP, lipid nanoparticle, business.industry, GOI, gene of Interest, Immunogenicity, General Medicine, Vaccination, Clinical research, biology.protein, Antibody, business, COVAC1 study Group, saRNA, saRNA, self-amplifying RNA, VEEV, Venezuelan equine encephalitis virus
Abstract

Summary: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0·1-10·0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p

Published
2022

2. Dexamethasone in Hospitalized Patients with Covid-19

Author

Susara Blunden, Alexander Mentzer, Tom Dymond, Nazima Pathan, Sabrina Helena Rossi, Calum Robertson, Robert Heyderman, Stacy Todd, Richard Haynes, Ahmad Abu-Arafeh, William Ricketts, Davinder Dosanjh, Simon Drysdale, Danyal Jajbhay, Grant D. Stewart, Andrew Ustianowski, Jane Blazeby, Ashton Barnett-Vanes, Nicholas Kametas, Elizabeth Bancroft, Ankur Gupta-Wright, Hanif Esmail, Gerard McKnight, Catherine Harwood, Anthony De soyza, Tuck-Kay Loke, Mili Estee Torok, Wei Shen Lim, Vishal Dey, Brendan Payne, Charles Christoph Roehr, Dominic Crocombe, Imogen Skene, Ran Wang, Martin Landray, Anna Bibby, Jamie Brannigan, Søren Kudsk-Iversen, Kathryn Puxty, Katrina Cathie, Maheshi Nirmala Ramasamy, Alan Montgomery, Louis Grandjean, Xin Hui Chan, Ben Gibbison, Dinesh Saralaya, Omer Elneima, Natalie Blencowe, Eleanor Mishra, Henry HL Wu, Roy Soiza, Patrick Lillie, Christian Alexander Linares, Simon Tso, Benjamin Caplin, Sarah Burge, Sakib Rokadiya, Manish Patel, Jamie Cooper, Lee Hoggett, Gareth Jones, Matt Morgan, Alex Horsley, Saul Faust, Martin Llewelyn, Alex Scott, Kim Hinshaw, Arvind Nune, Effrossyni Gkrania-Klotsas, Elizabeth Whittaker, Shaman Jhanji, Chetan Parmar, Chris Imray, Kathryn Rowan, Christopher Green, Mark Peters, Eoin O'Sullivan, Pallav Shah, Paul Dark, Luke Hodgson, Ryan Malcolm Hum, Varun Sarodaya, Chris Brightling, Pilar Rivera Ortega, Jonathan Emberson, Lucy Chappell, Ben Shelley, Richard Adams, Joseph Barker, John Kenneth Baillie, Manu Vatish, Jaki, Thomas [0000-0002-1096-188X], Apollo - University of Cambridge Repository, University of St Andrews. School of Medicine, National Institute for Health Research, and UK Research and Innovation

Subjects
deksametazon, Male, medicine.medical_treatment, Anti-Infective Agents/therapeutic use, Administration, Oral, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Rate ratio, Dexamethasone, law.invention, 0302 clinical medicine, Randomized controlled trial, Anti-Infective Agents, RA0421, law, RA0421 Public health. Hygiene. Preventive Medicine, Odds Ratio, 030212 general & internal medicine, 11 Medical and Health Sciences, Aged, 80 and over, Respiratory Distress Syndrome, Covid19, 3rd-DAS, General Medicine, Covid-19 -- drug therapy, Multicenter Study, Hospitalization, Randomized Controlled Trial, Injections, Intravenous, Original Article, Steroids, Drug Therapy, Combination, Female, covid-19 -- terapija z zdravili, medicine.drug, Dexamethasone/administration & dosage, RM, medicine.medical_specialty, Randomization, dexamethasone, Lung injury, COVID-19/drug therapy, 03 medical and health sciences, SDG 3 - Good Health and Well-being, General & Internal Medicine, Internal medicine, Journal Article, udc:616.9, medicine, Humans, Comparative Study, Glucocorticoids, Aged, Mechanical ventilation, SARS-CoV-2, business.industry, Oxygen Inhalation Therapy, Glucocorticoids/administration & dosage, COVID-19, Odds ratio, NIS, Length of Stay, Respiration, Artificial, United Kingdom, RM Therapeutics. Pharmacology, COVID-19 Drug Treatment, RECOVERY Collaborative Group, Respiratory failure, business, Anaesthesia Pain and Critical Care
Abstract

Supported by a grant (MC_PC_19056) to the University of Oxford from the Medical Research Council of United Kingdom Research and Innovation and the National Institute for Health Research (NIHR); and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. Dr. Lim is supported by core funding provided by NIHR Nottingham Biomedical Research Centre, Dr. Felton by the NIHR Manchester Biomedical Research Centre, and Dr. Jaki by a grant (MC_UU_0002/14) from the UK Medical Research Council and by an NIHR Senior Research Fellowship (NIHR-SRF-2015-08-001). BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P

Published
2021
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3. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Author

Susara Blunden, Alexander Mentzer, Tom Dymond, Robert Heyderman, Stacy Todd, Richard Haynes, Ahmad Abu-Arafeh, William Ricketts, Simon Drysdale, Danyal Jajbhay, Grant D. Stewart, Andrew Ustianowski, Jane Blazeby, Ashton Barnett-Vanes, Nicholas Kametas, Elizabeth Bancroft, Ankur Gupta-Wright, Hanif Esmail, Gerard McKnight, Catherine Harwood, Joe Fawke, Vivien Price, Tuck-Kay Loke, Kieran Nunn, Mili Estee Torok, Wei Shen Lim, Vishal Dey, Brendan Payne, Alexander Stockdale, Charles Christoph Roehr, Dominic Crocombe, Imogen Skene, Martin Landray, Anna Bibby, Jamie Brannigan, Padmasayee Papineni, Søren Kudsk-Iversen, Kathryn Puxty, Katrina Cathie, Maheshi Nirmala Ramasamy, Alan Montgomery, Louis Grandjean, Xin Hui Chan, Ben Gibbison, Cielito Caneja, Dinesh Saralaya, Omer Elneima, Charles Reynard, Natalie Blencowe, Eleanor Mishra, Henry HL Wu, Roy Soiza, Patrick Lillie, Paul Pfeffer, Christian Alexander Linares, Simon Tso, Benjamin Caplin, Sarah Burge, Sakib Rokadiya, Brunskill Nigel, Joel Tarning, Manish Patel, Jamie Cooper, Lee Hoggett, Nazima Pathan, Alex Horsley, Saul Faust, Martin Llewelyn, Alex Scott, Kim Hinshaw, Giorgio Calisti, Effrossyni Gkrania-Klotsas, Shaman Jhanji, Ben Burton, Anna Daunt, Chetan Parmar, Chris Imray, Christopher Green, Jonathan Underwood, Mark Peters, James A Watson, Eoin O'Sullivan, Pallav Shah, Paul Dark, Luke Hodgson, Ryan Malcolm Hum, Varun Sarodaya, Pilar Rivera Ortega, Jonathan Emberson, Ben Shelley, Richard Adams, Joseph Barker, John Kenneth Baillie, Manu Vatish, Tony Whitehouse, University of St Andrews. School of Medicine, Group, RECOVERY Collaborative, Jaki, Thomas [0000-0002-1096-188X], and Apollo - University of Cambridge Repository

Subjects
Male, medicine.medical_treatment, 030204 cardiovascular system & hematology, Rate ratio, law.invention, Pneumonia, viral/drug therapy, chloroquine, 0302 clinical medicine, Randomized controlled trial, law, RA0421, RA0421 Public health. Hygiene. Preventive Medicine, klorokin, 030212 general & internal medicine, Treatment Failure, Middle aged, Coronavirus infections/drug therapy, Aged, 80 and over, Incidence (epidemiology), General Medicine, 3rd-DAS, Middle Aged, hidroksiklorokin, Antiviral Agents/adverse effects, Covid-19 -- drug therapy, Hospitalization, Doxycycline, Hydroxychloroquine/adverse effects, Original Article, Female, Coronavirus Infections, covid-19 -- terapija z zdravili, medicine.drug, Hydroxychloroquine, medicine.medical_specialty, RM, hydroxychloroquine, Pneumonia, Viral, Antiviral Agents, 03 medical and health sciences, Betacoronavirus, SDG 3 - Good Health and Well-being, Internal medicine, udc:616.9, medicine, Humans, Pandemics, Aged, Mechanical ventilation, business.industry, SARS-CoV-2, COVID-19, NIS, Interim analysis, Respiration, Artificial, Confidence interval, RM Therapeutics. Pharmacology, COVID-19 Drug Treatment, Treatment failure, Relative risk, Respiration, artificial, business
Abstract

Supported by a grant (MC_PC_19056) to the University of Oxford from UK Research and Innovation and the NIHR and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. Publisher PDF

Published
2020
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4. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

Author

Maria Elena Maccari, Hassan Abolhassani, Asghar Aghamohammadi, Alessandro Aiuti, Olga Aleinikova, Catherine Bangs, Safa Baris, Federica Barzaghi, Helen Baxendale, Matthew Buckland, Siobhan O. Burns, Caterina Cancrini, Andrew Cant, Pascal Cathébras, Marina Cavazzana, Anita Chandra, Francesca Conti, Tanya Coulter, Lisa A. Devlin, J. David M. Edgar, Saul Faust, Alain Fischer, Marina Garcia Prat, Lennart Hammarström, Maximilian Heeg, Stephen Jolles, Elif Karakoc-Aydiner, Gerhard Kindle, Ayca Kiykim, Dinakantha Kumararatne, Bodo Grimbacher, Hilary Longhurst, Nizar Mahlaoui, Tomas Milota, Fernando Moreira, Despina Moshous, Anna Mukhina, Olaf Neth, Benedicte Neven, Alexandra Nieters, Peter Olbrich, Ahmet Ozen, Jana Pachlopnik Schmid, Capucine Picard, Seraina Prader, William Rae, Janine Reichenbach, Stephan Rusch, Sinisa Savic, Alessia Scarselli, Raphael Scheible, Anna Sediva, Svetlana O. Sharapova, Anna Shcherbina, Mary Slatter, Pere Soler-Palacin, Aurelie Stanislas, Felipe Suarez, Francesca Tucci, Annette Uhlmann, Joris van Montfrans, Klaus Warnatz, Anthony Peter Williams, Phil Wood, Sven Kracker, Alison Mary Condliffe, Stephan Ehl, Federal Ministry of Education and Research (Germany), Novartis, GlaxoSmithKline, University of Tehran, Service de Médecine Interne, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology, Regina Elena Cancer Institute, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Istanbul University, Addenbrookes Hospital, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 d'immuno-hématologie pédiatrique [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), Unité d'Immunologie Hématologie et Rhumatologie Pédiatrique [Necker, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Clinical Epidemiology, Deutches Krebsforschungszentrum, Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, European Laboratory for Food Induced Diseases, Università degli studi di Napoli Federico II, Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maccari, Maria Elena, Abolhassani, Hassan, Aghamohammadi, Asghar, Aiuti, Alessandro, Aleinikova, Olga, Bangs, Catherine, Baris, Safa, Barzaghi, Federica, Baxendale, Helen, Buckland, Matthew, Burns, Siobhan O., Cancrini, Caterina, Cant, Andrew, Cathebras, Pascal, Cavazzana, Marina, Chandra, Anita, Conti, Francesca, Coulter, Tanya, Devlin, Lisa A., Edgar, J. David M., Faust, Saul, Fischer, Alain, Prat, Marina Garcia, Hammarstrom, Lennart, Heeg, Maximilian, Jolles, Stephen, Karakoc-Aydiner, Elif, Kindle, Gerhard, Kiykim, Ayca, Kumararatne, Dinakantha, Grimbacher, Bodo, Longhurst, Hilary, Mahlaoui, Nizar, Milota, Tomas, Moreira, Fernando, Moshous, Despina, Mukhina, Anna, Neth, Olaf, Neven, Benedicte, Nieters, Alexandra, Olbrich, Peter, Ozen, Ahmet, Schmid, Jana Pachlopnik, Picard, Capucine, Prader, Seraina, Rae, William, Reichenbach, Janine, Rusch, Stephan, Savic, Sinisa, Scarselli, Alessia, Scheible, Raphael, Sediva, Anna, Sharapova, Svetlana O., Shcherbina, Anna, Slatter, Mary, Soler-Palacin, Pere, Stanislas, Aurelie, Suarez, Felipe, Tucci, Francesca, Uhlmann, Annette, van Montfrans, Joris, Warnatz, Klaus, Williams, Anthony Peter, Wood, Phil, Kracker, Sven, Condliffe, Alison Mary, Ehl, Stephan, Cathébras, Pascal, Hammarström, Lennart, Milota, Toma, Montfrans, Joris van, and Warnatz, Klau

Subjects
0301 basic medicine, Oncology, activated phosphoinositide 3-kinase δ syndrome, [SDV]Life Sciences [q-bio], SIROLIMUS, registry, Activated phosphoinositide 3-kinase δ syndrome, Immunology and Allergy, Registries, Young adult, Non-U.S. Gov't, Child, MUTATION, Societies, Medical, ComputingMilieux_MISCELLANEOUS, Research Support, Non-U.S. Gov't, Middle Aged, PIK3R1, 3. Good health, Europe, Settore MED/02, natural history, Child, Preschool, Perspective, Cohort, Sirolimus/therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Immunosuppressive Agents, medicine.drug, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Registry, activated phosphoinositide 3-kinase delta syndrome, Adolescent, Class I Phosphatidylinositol 3-Kinases, Primary Immunodeficiency Diseases, Immunology, Natural history, Research Support, Asymptomatic, 03 medical and health sciences, Young Adult, Medical, Internal medicine, Journal Article, medicine, Humans, Rapamycin, Preschool, Sirolimus, Immunologic Deficiency Syndromes/drug therapy, Cytopenia, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bronchiectasis, business.industry, rapamycin, Immunologic Deficiency Syndromes, PIK3CD, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune lymphoproliferative syndrome, Primary immunodeficiency, Immunosuppressive Agents/therapeutic use, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Societies, business, lcsh:RC581-607
Abstract

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies., This study was supported by the German Federal Ministry of Education and Research (BMBF 01E01303). The ESID-APDS registry is supported by the pharmaceutical companies Novartis, GlaxoSmithKline, and UCB UK.

Published
2018
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5. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study

Author

Federico Martinón-Torres, Antonio Salas, Irene Rivero-Calle, Miriam Cebey-López, Jacobo Pardo-Seco, Jethro A Herberg, Navin P Boeddha, Daniela S Klobassa, Fatou Secka, Stephane Paulus, Ronald de Groot, Luregn J Schlapbach, Gertjan J Driessen, Suzanne T Anderson, Marieke Emonts, Werner Zenz, Enitan D Carrol, Michiel Van der Flier, Michael Levin, Lachlan Coin, Stuart Gormley, Shea Hamilton, Jethro Herberg, Bernardo Hourmat, Clive Hoggart, Myrsini Kaforou, Vanessa Sancho-Shimizu, Victoria Wright, Amina Abdulla, Paul Agapow, Maeve Bartlett, Evangelos Bellos, Hariklia Eleftherohorinou, Rachel Galassini, David Inwald, Meg Mashbat, Stefanie Menikou, Sobia Mustafa, Simon Nadel, Rahmeen Rahman, Clare Thakker, Sumit Bokhandi, Sue Power, Heather Barham, Nazima Pathan, Jenna Ridout, Deborah White, Sarah Thurston, Saul Faust, Sanjay Patel, Jenni McCorkell, Patrick Davies, Lindsey Crate, Helen Navarra, Stephanie Carter, Raghu Ramaiah, Rekha Patel, Catherine Tuffrey, Andrew Gribbin, Sharon McCready, Mark Peters, Katie Hardy, Fran Standing, Lauren O'Neill, Eugenia Abelake, Akash Deep, Eniola Nsirim, Andrew Pollard, Louise Willis, Zoe Young, C Royad, Sonia White, Peter Marc Fortune, Phil Hudnott, Antonio Salas Ellacuriaga, Fernando Álvez González, Ruth Barral-Arca, María José Curras-Tuala, Natalia García, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Andrea Grela Beiroa, Antonio Justicia Grande, Pilar Leboráns Iglesias, Alba Elena Martínez Santos, Nazareth Martinón-Torres, José María Martinón Sánchez, Beatriz Morillo Gutiérrez, Belén Mosquera Pérez, Pablo Obando Pacheco, Sara Pischedda, Carmen Rodríguez-Tenreiro, Lorenzo Redondo-Collazo, Sonia Serén Fernández, María del Sol Porto Silva, Ana Vega, Lucía Vilanova Trillo, Susana Beatriz Reyes, María Cruz León León, Álvaro Navarro Mingorance, Xavier Gabaldó Barrios, Eider Oñate Vergara, Andrés Concha Torre, Ana Vivanco, Reyes Fernández, Francisco Giménez Sánchez, Miguel Sánchez Forte, Pablo Rojo, Jesús Ruiz Contreras, Alba Palacios, Cristina Epalza Ibarrondo, Elizabeth Fernández Cooke, Marisa Navarro, Cristina Álvarez Álvarez, María José Lozano, Eduardo Carreras, Sonia Brió Sanagustín, Olaf Neth, María del Carmen Martínez Padilla, Luis Manuel Prieto Tato, Sara Guillén, Laura Fernández Silveira, David Moreno, A. Marceline van Furth, Michiel van der Flier, Navin Prekash Boeddha, Gertjan JA Driessen, Jan A Hazelzet, Taco W Kuijpers, Dasja Pajkrt, Elisabeth AM Sanders, Diederik van de Beek, Arie van der Ende, Ria LA Philipsen, Abdul OA Adeel, Meike A Breukels, Danielle MC Brinkman, Carla CMM de Korte, Esther de Vries, Wouter J de Waal, Roel Dekkers, Anouk Dings-Lammertink, Rienus A Doedens, Albertine E Donker, Mieke Dousma, Tina E Faber, G Peter JM Gerrits, Jan AM Gerver, Jojanneke Heidema, Jenneke Homan-van der Veen, Monique AM Jacobs, Nicolaas JG Jansen, Pawel Kawczynski, Kristine Klucovska, Martin CJ Kneyber, Yvonne Koopman-Keemink, Veerle J Langenhorst, José Leusink, Bettina F Loza, Istvan T Merth, Carien J Miedema, Chris Neeleman, Jeroen G Noordzij, Charles C Obihara, A Lidy T van Overbeek - van Gils, Geriska H Poortman, Steph T Potgieter, Joke Potjewijd, Philippe PR Rosias, Tom Sprong, Gavin W ten Tussher, Boony J Thio, Gerdien A Tramper-Stranders, Marcel van Deuren, Henny van der Meer, Andre JM van Kuppevelt, Anne-Marie van Wermeskerken, Wim A Verwijs, Tom FW Wolfs, Luregn Jan Schlapbach, Philipp Agyeman, Christoph Aebi, Christoph Berger, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Paul Hasters, Christa Relly, Walter Baer, Enitan Carrol, Stéphane Paulus, Hannah Frederick, Rebecca Jennings, Joanne Johnston, Rhian Kenwright, Colin G Fink, Elli Pinnock, Rachel Sarah Agbeko, Kalifa A Bojang, Isatou Sarr, Ngange Kebbeh, Gibbi Sey, Momodou Saidykhan, Fatoumata Cole, Gilleh Thomas, Martin Antonio, Daniela Sabine Klobassa, Alexander Binder, Nina Alexandra Schweintzger, Manfred Sagmeister, Hinrich Baumgart, Markus Baumgartner, Uta Behrends, Ariane Biebl, Robert Birnbacher, Jan-Gerd Blanke, Carsten Boelke, Kai Breuling, Jürgen Brunner, Maria Buller, Peter Dahlem, Beate Dietrich, Ernst Eber, Johannes Elias, Josef Emhofer, Rosa Etschmaier, Sebastian Farr, Ylenia Girtler, Irina Grigorow, Konrad Heimann, Ulrike Ihm, Zdenek Jaros, Hermann Kalhoff, Wilhelm Kaulfersch, Christoph Kemen, Nina Klocker, Bernhard Köster, Benno Kohlmaier, Eleni Komini, Lydia Kramer, Antje Neubert, Daniel Ortner, Lydia Pescollderungg, Klaus Pfurtscheller, Karl Reiter, Goran Ristic, Siegfried Rödl, Andrea Sellner, Astrid Sonnleitner, Matthias Sperl, Wolfgang Stelzl, Holger Till, Andreas Trobisch, Anne Vierzig, Ulrich Vogel, Christina Weingarten, Stefanie Welke, Andreas Wimmer, Uwe Wintergerst, Daniel Wüller, Andrew Zaunschirm, Ieva Ziuraite, Veslava Žukovskaja, Posfay Barbe, Klara, Pediatrics, Huisarts & Ziekenhuis, Tranzo, Scientific center for care and wellbeing, ARD - Amsterdam Reproduction and Development, AII - Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, ANS - Neuroinfection & -inflammation, Neurology, Medical Microbiology and Infection Prevention, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), The European Society for Paediatric Infectious Diseases, Meningitis Research Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), University of Zurich, and Martinón-Torres, Federico

Subjects
Male, Pediatrics, RJ101, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Severity of Illness Index, Cohort Studies, 0302 clinical medicine, Cost of Illness, Developmental and Educational Psychology, 030212 general & internal medicine, Prospective Studies, Sepsis/epidemiology, Prospective cohort study, Child, media_common, ddc:618, Bacterial Infections, Europe, Child, Preschool, Cohort, Female, Algorithms, Cohort study, medicine.medical_specialty, 610 Medicine & health, Europe/epidemiology, Sepsis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 030225 pediatrics, Severity of illness, medicine, media_common.cataloged_instance, Humans, 2735 Pediatrics, Perinatology and Child Health, European union, Preschool, Disease burden, 3204 Developmental and Educational Psychology, business.industry, Infant, Newborn, Infant, medicine.disease, Newborn, Pneumonia, 10036 Medical Clinic, Pediatrics, Perinatology and Child Health, business, Bacterial Infections/epidemiology
Abstract

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; pInterpretation Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients.

Published
2018
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