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      Updated diagnosis, treatment and prevention of COVID-19 in children: experts’ consensus statement (condensed version of the second edition)

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      1 , , 1 , , 2 , 3 , 4 , , 5 , 6 , 7 , 8 , 1 , 9 , 10 , 2 , 11 , 12 , 13 , 7 , 14 , 15 , 16 , 17 , 18 , 5 , 19 , 20 , 21 , 22 , 1 , 23 , 24 , China National Clinical Research Center for Respiratory Diseases, National Center for Children’s Health, Beijing, China, Group of Respirology, Chinese Pediatric Society, Chinese Medical Association, Chinese Medical Doctor Association Committee on Respirology Pediatrics, China Medicine Education Association Committee on Pediatrics, Chinese Research Hospital Association Committee on Pediatrics, China Non-government Medical Institutions Association Committee on Pediatrics, China Association of Traditional Chinese Medicine, Committee on Children’s Health and Medicine Research, China News of Drug Information Association, Committee on Children’s Safety Medication, Global Pediatric Pulmonology Alliance
      World Journal of Pediatrics
      Springer Singapore
      Children, COVID-19, Infection, SARS-CoV-2, Treatment

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          Abstract

          In the early February, 2020, we called up an experts’ committee with more than 30 Chinese experts from 11 national medical academic organizations to formulate the first edition of consensus statement on diagnosis, treatment and prevention of coronavirus disease 2019 (COVID-19) in children, which has been published in this journal. With accumulated experiences in the diagnosis and treatment of COVID-19 in children, we have updated the consensus statement and released the second edition recently. The current version in English is a condensed version of the second edition of consensus statement on diagnosis, treatment and prevention of COVID-19 in children. In the current version, diagnosis and treatement criteria have been optimized, and early identification of severe and critical cases is highlighted. The early warning indicators for severe pediatric cases have been summarized which is utmost important for clinical practice. This version of experts consensus will be valuable for better prevention, diagnosis and treatment of COVID-19 in children worldwide.  

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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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            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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              Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement

              Since the outbreak of 2019 novel coronavirus infection (2019-nCoV) in Wuhan City, China, by January 30, 2020, a total of 9692 confirmed cases and 15,238 suspected cases have been reported around 31 provinces or cities in China. Among the confirmed cases, 1527 were severe cases, 171 had recovered and been discharged at home, and 213 died. And among these cases, a total of 28 children aged from 1 month to 17 years have been reported in China. For standardizing prevention and management of 2019-nCoV infections in children, we called up an experts’ committee to formulate this experts’ consensus statement. This statement is based on the Novel Coronavirus Infection Pneumonia Diagnosis and Treatment Standards (the fourth edition) (National Health Committee) and other previous diagnosis and treatment strategies for pediatric virus infections. The present consensus statement summarizes current strategies on diagnosis, treatment, and prevention of 2019-nCoV infection in children.
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                Author and article information

                Contributors
                kunlingshen1717@163.com
                yyh628628@sina.coms
                zhao_wh2004@hotmail.com
                Journal
                World J Pediatr
                World J Pediatr
                World Journal of Pediatrics
                Springer Singapore (Singapore )
                1708-8569
                1867-0687
                24 April 2020
                : 1-8
                Affiliations
                [1 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, China National Clinical Research Center for Respiratory Diseases, , Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, ; Beijing, China
                [2 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Institute of Infectious Disease, , Beijing Ditan Hospital, Capital Medical University, ; Beijing, China
                [3 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Center of Hematologic Oncology, National Center for Children’s Health, , Beijing Children’s Hospital, Capital Medical University, ; Beijing, China
                [4 ]GRID grid.413247.7, Department of Pediatrics, , Zhongnan Hospital of Wuhan University, ; Wuhan, China
                [5 ]GRID grid.412632.0, ISNI 0000 0004 1758 2270, Department of Pediatrics, , Renmin Hospital of Wuhan University, ; Wuhan, China
                [6 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Respiratory Medicine, , Wuhan Children’s Hospital, Tongji Medical College of Huazhong University of Science and Technology, ; Wuhan, China
                [7 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Pediatrics, , Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, ; Wuhan, China
                [8 ]GRID grid.452787.b, ISNI 0000 0004 1806 5224, Department of Respiratory Medicine, , Shenzhen Children’s Hospital, ; Shenzhen, China
                [9 ]China National Clinical Research Center for Respiratory Diseases, Beijing Institute of Pediatrics, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, Beijing, 2019RU016 China
                [10 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Neurology, , Wuhan Children’s Hospital, Tongji Medical College of Huazhong University of Science and Technology, ; Wuhan, China
                [11 ]Institute of Hospital Management, Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, China
                [12 ]GRID grid.412467.2, ISNI 0000 0004 1806 3501, Department of Pediatric Respiratory, , Shengjing Hospital of China Medical University, ; Shenyang, China
                [13 ]GRID grid.412793.a, ISNI 0000 0004 1799 5032, Department of Pediatrics, , Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, China
                [14 ]Department of Respiratory Medicine, Children’s Hospital of Shanghai, Shanghai, China
                [15 ]GRID grid.413428.8, ISNI 0000 0004 1757 8466, Department of Respiratory Medicine, , Guangzhou Women and Children’s Medical Center, ; Guangzhou, China
                [16 ]GRID grid.452787.b, ISNI 0000 0004 1806 5224, Department of Infectious Diseases, , Shenzhen Children’s Hospital, ; Shenzhen, China
                [17 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Office of Infection Management, , Wuhan Children’s Hospital, Tongji Medical College of Huazhong University of Science and Technology, ; Wuhan, China
                [18 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Infectious Diseases, , Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, ; Wuhan, China
                [19 ]GRID grid.459540.9, ISNI 0000 0004 1791 4503, Department of Pediatrics, , Guizhou Provincial People’s Hospital, ; Guiyang, China
                [20 ]GRID grid.411472.5, ISNI 0000 0004 1764 1621, Department of Pediatrics, , Peking University First Hospital, ; Beijing, China
                [21 ]GRID grid.413247.7, Department of Obstetrics, , Zhongnan Hospital of Wuhan University, ; Wuhan, China
                [22 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Radiographic Center, , Wuhan Children’s Hospital, Tongji Medical College of Huazhong University of Science and Technology, ; Wuhan, China
                [23 ]GRID grid.410318.f, ISNI 0000 0004 0632 3409, Institute of Basic Research in Clinical Medicine, , China Academy of Chinese Medical Sciences, ; Beijing, China
                [24 ]GRID grid.477514.4, Department of Pediatrics, , Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, ; Shenyang, China
                Article
                362
                10.1007/s12519-020-00362-4
                7180653
                32333248
                be7d6303-53aa-42d7-94f1-b3a9b11b3d77
                © Children's Hospital, Zhejiang University School of Medicine 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 16 March 2020
                : 24 March 2020
                Categories
                Review Article

                children,covid-19,infection,sars-cov-2,treatment
                children, covid-19, infection, sars-cov-2, treatment

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