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      COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

      research-article
      , MD a , * , , PhD b , f , * , , Prof, PhD c , d , e , f , , PhD c , , PhD g , , PhD g , , PhD h , , PhD h , , MD i , , MD i , , MD j , , MD k , , FRCPCH l , m , , PhD n , , MD n , , PhD o , , MD o , , MD p , , MD p , , Prof, MD q , , PhD q , r , , MD s , , MD t , , PhD t , , MD b , f , , MD u , , MD u , , MD v , , FRCPCH w , , MD a , , PhD x , , PhD m , r , y , * , ptbnet COVID-19 Study Group
      The Lancet. Child & Adolescent Health
      Elsevier Ltd.
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          Summary

          Background

          To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic.

          Methods

          This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network—the Paediatric Tuberculosis Network European Trials Group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission.

          Findings

          582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2–11, range 1–34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72–14·87; p=0·0035), male sex (2·12, 1·06–4·21; p=0·033), pre-existing medical conditions (3·27, 1·67–6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16–21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir–ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20–1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support.

          Interpretation

          COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed.

          Funding

          ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.

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          Most cited references32

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          Is Open Access

          The species Severe acute respiratory syndrome-related coronavirus : classifying 2019-nCoV and naming it SARS-CoV-2

          The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.
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            A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

            Abstract Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2) to the fraction of inspired oxygen (Fio 2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)
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              Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

              Summary Background Previous studies on the pneumonia outbreak caused by the 2019 novel coronavirus disease (COVID-19) were based on information from the general population. Limited data are available for pregnant women with COVID-19 pneumonia. This study aimed to evaluate the clinical characteristics of COVID-19 in pregnancy and the intrauterine vertical transmission potential of COVID-19 infection. Methods Clinical records, laboratory results, and chest CT scans were retrospectively reviewed for nine pregnant women with laboratory-confirmed COVID-19 pneumonia (ie, with maternal throat swab samples that were positive for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) who were admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from Jan 20 to Jan 31, 2020. Evidence of intrauterine vertical transmission was assessed by testing for the presence of SARS-CoV-2 in amniotic fluid, cord blood, and neonatal throat swab samples. Breastmilk samples were also collected and tested from patients after the first lactation. Findings All nine patients had a caesarean section in their third trimester. Seven patients presented with a fever. Other symptoms, including cough (in four of nine patients), myalgia (in three), sore throat (in two), and malaise (in two), were also observed. Fetal distress was monitored in two cases. Five of nine patients had lymphopenia (<1·0 × 10⁹ cells per L). Three patients had increased aminotransferase concentrations. None of the patients developed severe COVID-19 pneumonia or died, as of Feb 4, 2020. Nine livebirths were recorded. No neonatal asphyxia was observed in newborn babies. All nine livebirths had a 1-min Apgar score of 8–9 and a 5-min Apgar score of 9–10. Amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from six patients were tested for SARS-CoV-2, and all samples tested negative for the virus. Interpretation The clinical characteristics of COVID-19 pneumonia in pregnant women were similar to those reported for non-pregnant adult patients who developed COVID-19 pneumonia. Findings from this small group of cases suggest that there is currently no evidence for intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy. Funding Hubei Science and Technology Plan, Wuhan University Medical Development Plan.
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                Author and article information

                Contributors
                Journal
                Lancet Child Adolesc Health
                Lancet Child Adolesc Health
                The Lancet. Child & Adolescent Health
                Elsevier Ltd.
                2352-4642
                2352-4650
                25 June 2020
                25 June 2020
                Affiliations
                [a ]Department of Paediatric and Adolescent Medicine, National Reference Centre for Childhood Tuberculosis, Wilhelminenspital, Vienna, Austria
                [b ]Department of Paediatric Infectious Diseases, University Hospital Gregorio Marañón and Gregorio Marañón Research Institute, Madrid, Spain
                [c ]Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d'Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain
                [d ]Departament de Pediatria, Universitat de Barcelona, Barcelona, Spain
                [e ]Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, Spain
                [f ]Red de Investigación Translacional en Infectología Pediátrica, Madrid, Spain
                [g ]Academic Department of Paediatrics, Bambino Gesù Children's Hospital, Rome, Italy
                [h ]Children's Clinic, Department of Pulmonary Diseases, MHATLD “St Sofia”, Medical University Sofia, Sofia, Bulgaria
                [i ]Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
                [j ]Department of Paediatric Pulmonology, University Medical Centre Ljubljana, Ljubljana, Slovenia
                [k ]Section of Paediatrics, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
                [l ]Department of Paediatric Infectious Diseases, Great Ormond Street Hospital, London, UK
                [m ]Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
                [n ]Paediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Spain
                [o ]Medical and Surgical Science Department, S Orsola University Hospital, Bologna, Italy
                [p ]Paediatric Infectious Diseases Unit, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
                [q ]Department of Paediatric Infectious Diseases and Vaccinology, University of Basel Children's Hospital, Basel, Switzerland
                [r ]Department of Paediatrics, Royal Children's Hospital Melbourne, University of Melbourne, Melbourne, Australia
                [s ]Department of Paediatrics, Leicester Children's Hospital, Leicester, UK
                [t ]Department of Paediatric Infectious Diseases, University Hospital for Infectious Diseases, Zagreb, Croatia
                [u ]Department of Paediatric Infectious Diseases, CHC Montlegia, Liège, Belgium
                [v ]Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy
                [w ]Birmingham Chest Clinic and Heartlands Hospital, University Hospitals Birmingham, Birmingham, UK
                [x ]Department of Paediatric Pulmonology, Ruhr University Bochum, Bochum, Germany
                [y ]Department of Paediatric Infectious Diseases & Immunology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
                Author notes
                [* ]Correspondence to: Dr Marc Tebruegge, Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK m.tebruegge@ 123456ucl.ac.uk
                [*]

                Contributed equally

                [†]

                Members are listed at the end of the Article

                Article
                S2352-4642(20)30177-2
                10.1016/S2352-4642(20)30177-2
                7316447
                32593339
                7ce4b851-2191-4d78-984a-952dd1ae6518
                © 2020 Elsevier Ltd. All rights reserved.

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