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      Epidemiology of COVID-19 infection in young children under five years: A systematic review and meta-analysis

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          Abstract

          Introduction

          Emerging evidence suggests young children are at greater risk of COVID-19 infection than initially predicted. However, a comprehensive understanding of epidemiology of COVID-19 infection in young children under five years, the most at-risk age-group for respiratory infections, remain unclear. We conducted a systematic review and meta-analysis of epidemiological and clinical characteristics of COVID-19 infection in children under five years.

          Method

          Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses , we searched several electronic databases (Pubmed, EMBASE, Web of Science, and Scopus) with no language restriction for published epidemiological studies and case-reports reporting laboratory-confirmed COVID-19 infection in children under five years until June 4, 2020. We assessed pooled prevalence for key demographics and clinical characteristics using Freeman-Tukey double arcsine random-effects model for studies except case-reports. We evaluated risk of bias separately for case-reports and other studies.

          Results

          We identified 1,964 articles, of which, 65 articles were eligible for systematic review that represented 1,214 children younger than five years with laboratory-confirmed COVID-19 infection. The pooled estimates showed that 50% young COVID-19 cases were infants (95% CI: 36% − 63%, 27 studies); 53% were male (95% CI: 41% − 65%, 24 studies); 43% were asymptomatic (95% CI: 15% − 73%, 9 studies) and 7% (95% CI: 0% − 30%, 5 studies) had severe disease that required intensive-care-unit admission. Of 139 newborns from COVID-19 infected mothers, five (3.6%) were COVID-19 positive. There was only one death recorded.

          Discussion

          This systematic review reports the largest number of children younger than five years with COVID-19 infection till date. Our meta-analysis shows nearly half of young COVID-19 cases were asymptomatic and half were infants, highlighting the need for ongoing surveillance to better understand the epidemiology, clinical pattern, and transmission of COVID-19 to develop effective preventive strategies against COVID-19 disease in young paediatric population.

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          Puja Mehta, Daniel McAuley, Michael Brown … (2020)
          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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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

            Huijun Chen, Juanjuan Guo, Chen Wang … (2020)
            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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              SARS-CoV-2 Infection in Children

              Xiaoxia Lu, Liqiong Zhang, Hui Du … (2020)
              To the Editor: As of March 10, 2020, the 2019 novel coronavirus (SARS-CoV-2) has been responsible for more than 110,000 infections and 4000 deaths worldwide, but data regarding the epidemiologic characteristics and clinical features of infected children are limited. 1-3 A recent review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that less than 1% of the cases were in children younger than 10 years of age. 2 In order to determine the spectrum of disease in children, we evaluated children infected with SARS-CoV-2 and treated at the Wuhan Children’s Hospital, the only center assigned by the central government for treating infected children under 16 years of age in Wuhan. Both symptomatic and asymptomatic children with known contact with persons having confirmed or suspected SARS-CoV-2 infection were evaluated. Nasopharyngeal or throat swabs were obtained for detection of SARS-CoV-2 RNA by established methods. 4 The clinical outcomes were monitored up to March 8, 2020. Of the 1391 children assessed and tested from January 28 through February 26, 2020, a total of 171 (12.3%) were confirmed to have SARS-CoV-2 infection. Demographic data and clinical features are summarized in Table 1. (Details of the laboratory and radiologic findings are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) The median age of the infected children was 6.7 years. Fever was present in 41.5% of the children at any time during the illness. Other common signs and symptoms included cough and pharyngeal erythema. A total of 27 patients (15.8%) did not have any symptoms of infection or radiologic features of pneumonia. A total of 12 patients had radiologic features of pneumonia but did not have any symptoms of infection. During the course of hospitalization, 3 patients required intensive care support and invasive mechanical ventilation; all had coexisting conditions (hydronephrosis, leukemia [for which the patient was receiving maintenance chemotherapy], and intussusception). Lymphopenia (lymphocyte count, <1.2×109 per liter) was present in 6 patients (3.5%). The most common radiologic finding was bilateral ground-glass opacity (32.7%). As of March 8, 2020, there was one death. A 10-month-old child with intussusception had multiorgan failure and died 4 weeks after admission. A total of 21 patients were in stable condition in the general wards, and 149 have been discharged from the hospital. This report describes a spectrum of illness from SARS-CoV-2 infection in children. In contrast with infected adults, most infected children appear to have a milder clinical course. Asymptomatic infections were not uncommon. 2 Determination of the transmission potential of these asymptomatic patients is important for guiding the development of measures to control the ongoing pandemic.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Vaccine
                Journal ID (iso-abbrev): Vaccine
                Title: Vaccine
                Publisher: Elsevier Ltd.
                ISSN (Print): 0264-410X
                ISSN (Electronic): 1873-2518
                Publication date PMC-release: 5 December 2020
                Publication date (Print): 22 January 2021
                Publication date (Electronic): 5 December 2020
                Volume: 39
                Issue: 4
                Pages: 667-677
                Affiliations
                [a ]Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Western Australia, Australia
                [b ]School of Public Health, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia
                [c ]Program for Emerging Infections, Infectious Diseases Division, icddr,b, Bangladesh
                [d ]School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
                [e ]School of Public Health and Community Medicine, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
                [f ]The Royal Veterinary College, University of London, Hatfield, Hertfordshire, AL9 7TA, UK
                [g ]Respiratory Department, Sydney Children’s Hospital, Sydney, New South Wales, Australia
                Author notes
                [* ]Corresponding author at: Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands WA 6009, Australia.
                [1]

                Contributed equally.

                Article
                Publisher Item ID: S0264-410X(20)31570-X
                DOI: 10.1016/j.vaccine.2020.11.078
                PMC ID: 7833125
                PubMed ID: 33342635
                SO-VID: 3697ed85-d447-4a11-9afc-ae1a051f2545
                Copyright © © 2020 Elsevier Ltd. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 25 August 2020
                Date revision received : 16 November 2020
                Date accepted : 30 November 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: covid-19,children younger than five years,covid-19 newborns
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: covid-19, children younger than five years, covid-19 newborns

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