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      Clinical, radiological and laboratory characteristics of pediatric patients with COVID-19: Living systematic review Translated title: Características clínicas, radiológicas y de laboratorio en pacientes pediátricos con COVID-19. Revisión sistemática viva

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          Abstract

          Abstract Introduction: Since the first COVID-19 cases were reported, the disease's clinical and epidemiological characteristics have continuously been studied, although they have not been yet defined. Objective: To estimate the epidemiological profile of pediatric patients with COVID-19, as well as their clinical, laboratory and radiological characteristics. Materials and methods: A living systemic review was conducted in the PubMed, Scopus and SciELO databases. Observational studies describing clinical, radiological, and laboratory characteristics of pediatric patients with COVID-19 and published between January 1, 2020, and July 20, 2020, were considered for the search; there were no language restrictions. Government, epidemiological, and pre-print papers were also considered. Meta-analyses of single proportion (frequentist approach) and two proportions (Bayesian method) were carried out. The study registration and protocol are available at https://osf.io/y43wm and https://osf.io/r8ktv, respectively. Results: 13 studies, with a total of 9 152 patients, were retrieved. The Bayesian meta-analysis reported that males are more affected by the disease: OR 1.24 (HDI95%: 1.09-1.4). The proportion results calculated by means of the frequentist meta-analysis are: 52% cough (95%CI: 50-55), 0% death (95%CI: 0-0.1), 16% high aspartate transaminase levels (95%CI: 13-19), and 60% lung changes observed in chest X-ray (95%CI: 57-64). Conclusions: Based on the current data, it is not possible to describe accurately the clinical and epidemiological characteristics of COVID-19 in the pediatric population. However, evidence suggests that males are more affected by the disease and that lung alterations in imaging studies are more frequent than clinical signs such as cough and fever. Laboratory test results are not conclusive and show that different organs and systems of the human body may be affected by SARS-CoV-2. The results reported here must be compared to prospective controlled studies conducted in larger samples and a more rigorous design.

          Translated abstract

          Resumen Introducción. Desde que se reportaron los primeros casos de COVID-19, sus características clínicas y epidemiológicas han sido constantemente estudiadas, pero aún no han sido definidas. Objetivo. Estimar el perfil epidemiológico, así como las características clínicas, radiológicas y de laboratorio en pacientes pediátricos con COVID-19. Materiales y métodos. Se realizó una revisión sistemática viva en las bases de datos PubMed, Scopus y SciELO; para la búsqueda se consideraron estudios observacionales publicados entre enero 1 de 2020 y julio 20 de 2020, sin restricción de idioma, que describieran características clínicas, radiológicas y de laboratorio en población pediátrica con COVID-19; también se incluyeron reportes gubernamentales y epidemiológicos, y artículos publicados en formato pre-print. Se realizaron metaanálisis de proporción única (método frecuentista) y de dos proporciones (método bayesiano). El registro y el protocolo del estudio están disponibles en https://osf.io/y43wm y https://osf.io/r8ktv, respectivamente. Resultados. Se encontraron 13 estudios, con un total de 9 152 pacientes. El metaanálisis bayesiano reportó una mayor afectación del sexo masculino: OR: 1.2 (HDI95%: 1.09-1.4). Los resultados de la proporción calculada por el metaanálisis frecuentista fueron: tos 52% (IC95%: 50-55), muerte 0% (IC95%: 0-0.1), niveles elevados de aspartato aminotransferasa 16% (IC95%: 13-19) y alteraciones pulmonares evidenciadas mediante estudios de imagen 60% (IC95%: 57-64). Conclusiones. Con los datos actuales no es posible describir con exactitud las características clínicas y epidemiológicas de la COVID-19 en población pediátrica. Sin embargo, existen indicios de una mayor afectación al sexo masculino, y de que las anormalidades pulmonares detectadas en radiografías y tomografías del tórax son más frecuentes que signos clínicos como la tos y la fiebre. Los resultados de laboratorio no son concluyentes y reflejan que diferentes órganos y sistemas son afectados por el SARS-CoV-2. Los hallazgos del presente estudio deben ser contrastados con estudios prospectivos controlados, con un mayor número de pacientes y un diseño más riguroso.

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          Pathological findings of COVID-19 associated with acute respiratory distress syndrome

          Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV)1, 2 was reported in Wuhan, China, 2 which has subsequently affected 26 countries worldwide. In general, COVID-19 is an acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and over 1524 deaths. However, no pathology has been reported due to barely accessible autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration. Our findings will facilitate understanding of the pathogenesis of COVID-19 and improve clinical strategies against the disease. A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of fever, chills, cough, fatigue and shortness of breath. He reported a travel history to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure 1 ). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had COVID-19. Figure 1 Timeline of disease course according to days from initial presentation of illness and days from hospital admission, from Jan 8–27, 2020 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. He was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. He was given interferon alfa-2b (5 million units twice daily, atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone (80 mg twice daily, intravenously) was administered to attenuate lung inflammation. Laboratory tests results are listed in the appendix (p 4). After receiving medication, his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy (60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms had still not improved, but oxygen saturation remained above 95%. In the afternoon of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given invasive ventilation, chest compression, and adrenaline injection. Unfortunately, the rescue was not successful, and he died at 18:31 (Beijing time). Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B ). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Figure 2 Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C), and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D). Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient. X-ray images showed rapid progression of pneumonia and some differences between the left and right lung. In addition, the liver tissue showed moderate microvesicular steatosis and mild lobular activity, but there was no conclusive evidence to support SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might not directly impair the heart. Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2 pneumonia, 1 according to our pathological findings of pulmonary oedema and hyaline membrane formation, timely and appropriate use of corticosteroids together with ventilator support should be considered for the severe patients to prevent ARDS development. Lymphopenia is a common feature in the patients with COVID-19 and might be a critical factor associated with disease severity and mortality. 3 Our clinical and pathological findings in this severe case of COVID-19 can not only help to identify a cause of death, but also provide new insights into the pathogenesis of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely therapeutic strategy for similar severe patients and reduce mortality. This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on February 25, 2020
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            How to perform a meta-analysis with R: a practical tutorial

            Meta-analysis is of fundamental importance to obtain an unbiased assessment of the available evidence. In general, the use of meta-analysis has been increasing over the last three decades with mental health as a major research topic. It is then essential to well understand its methodology and interpret its results. In this publication, we describe how to perform a meta-analysis with the freely available statistical software environment R, using a working example taken from the field of mental health. R package meta is used to conduct standard meta-analysis. Sensitivity analyses for missing binary outcome data and potential selection bias are conducted with R package metasens. All essential R commands are provided and clearly described to conduct and report analyses. The working example considers a binary outcome: we show how to conduct a fixed effect and random effects meta-analysis and subgroup analysis, produce a forest and funnel plot and to test and adjust for funnel plot asymmetry. All these steps work similar for other outcome types. R represents a powerful and flexible tool to conduct meta-analyses. This publication gives a brief glimpse into the topic and provides directions to more advanced meta-analysis methods available in R.
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              SARS-CoV-2 Infection in Children

              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
                rfmun
                Revista de la Facultad de Medicina
                rev.fac.med.
                Universidad Nacional de Colombia (Bogotá, Distrito Capital, Colombia )
                0120-0011
                March 2021
                : 69
                : 1
                : e203
                Affiliations
                [3] Quito orgnameUniversidad San Francisco de Quito Ecuador
                [1] Quito Quito orgnameUniversidad Central del Ecuador Ecuador
                [2] São Paulo São Paulo orgnameUniversidade de São Paulo Brazil
                Article
                S0120-00112021000100203 S0120-0011(21)06900100203
                10.15446/revfacmed.v69n1.90222
                539a1cb8-c6d9-48d0-be80-0db61e96ff5a

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 30 August 2020
                : 03 November 2020
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 53, Pages: 0
                Product

                SciELO Colombia

                Categories
                Original papers

                Children,Radiología (DeCS),Laboratorio,Signos y síntomas,COVID-19,Niños,Radiology (MeSH),Laboratory,Signs and symptoms

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