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      The severity of COVID-19 in children on immunosuppressive medication

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          Abstract

          The number of people with coronavirus disease 2019 (COVID-19) during this ongoing pandemic is rising rapidly. It is already clear that children have considerably better outcomes than adults (particularly older adults ≥70 years), with a mortality of less than 1%.1, 2 In the adult population, those with pulmonary or cardiac comorbidities have worse outcomes than those without these comorbidities. 1 We are currently managing an ongoing survey that includes children aged 0–19 years with kidney disease on immunosuppressive medication who are diagnosed with COVID-19. The study was initiated by the European Rare Kidney Disease Reference Network and is supported by the European, Asian, and international paediatric nephrology societies. The members of these societies and the members of the listserv, Pedneph, were asked at regular intervals to include any child in their care fulfilling these criteria. The information was collected in a totally anonymised manner. Within 6 weeks after March 15, 2020, 18 children from 16 paediatric nephrology centres across 11 countries (ie, Spain, Switzerland, China, the UK, Germany, France, Sweden, Colombia, the USA, Iran, and Belgium) who met our criteria were recorded. We report on the underlying diagnoses, ongoing immunosuppressive treatment, clinical symptoms, and outcomes (table ). Table Demographics, immunosuppressive treatments, and outcomes of children with kidney disease and COVID-19 Participants with COVID-19 (n=18) Demographics Median age, years 11·5 (6·0–14·0) Sex Boys 11 (61%) Girls 7 (39%) Underlying kidney disease and reason for immunosuppression Kidney transplantation 11 (61%) Nephrotic syndrome 3 (17%) Antineutrophil cytoplasmic antibody-associated vasculitis 2 (11%) Atypical haemolytic uraemic syndrome 1 (6%) End-stage kidney disease with inflammatory bowel disease 1 (6%) Immunosuppressive treatments Glucocorticoids 12 (67%) Tacrolimus 12 (67%) Mycophenolate Mofetil 9 (50%) Rituximab 3 (17%) Azathioprine 2 (11%) Basiliximab 1 (6%) Cyclophosphamide 1 (6%) Ciclosporin 1 (6%) Everolimus 1 (6%) Adalimumab 1 (6%) Eculizumab 1 (6%) COVID-19 Symptoms Fever 13 (72%) Cough 11 (61%) Rhinitis 5 (28%) Diarrhoea 3 (17%) Shortness of breath 0 (0%) Median time since the onset of illness at the time of reporting, days 5·0 (2·0–9·5) Maximal respiratory support required High-flow nasal cannula oxygen 1 (6%) Supplemental face mask oxygen 2 (11%) None 15 (83%) Outcome Admitted to intensive care 0 (0%) Admitted to hospital 11 (61%) Not admitted to hospital at any point 7 (39%) Data are n (%) or median (IQR). COVID-19=coronavirus disease 2019. These data from a small number of children suggests that even children receiving immunosuppressive treatment for various indications appear to have a mild clinical course of COVID-19. Similarly, a study with eight children with inflammatory bowel disease found that all children diagnosed with Covid-19 had a mild infection, despite treatment with immunomodulators, biologics, or both. 3 The low number of children thus far in our global survey is consistent with a study from Lombardy, Italy. 4 Grasselli and colleagues 4 described 1591 patients who needed treatment in intensive care. 4 Of those 1591 patients, only four were younger than 20 years. At the time of publication, none of these four young people had died, but two still needed treatment in intensive care. Three of these four individuals had some undefined comorbidity. Although with a survey administered online there is a risk of underreporting because not all clinicians might receive it, we believe that the widespread dissemination of this survey across multiple international organisations would mean that most severe cases of COVID-19 in children with kidney disease would be reported. Analysis of our data across four countries where survey dissemination and case reporting is known to be high suggests that the incidence of COVID-19 in the paediatric kidney transplant population is similar to the background incidence of COVID-19 in the general population (appendix). However, we accept that this type of survey does not have a truly systematic approach to identifying cases, which limits our study. Studies with higher numbers of children are needed to confirm these early findings and identify any long-term consequences of, and the level of immunity that might be acquired from, COVID-19. We therefore encourage readers of this Correspondence to report all children under their care who fulfil our inclusion criteria to our study.

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          Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy

          In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged in China and has spread globally, creating a pandemic. Information about the clinical characteristics of infected patients who require intensive care is limited.
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            Estimates of the severity of coronavirus disease 2019: a model-based analysis

            Summary Background In the face of rapidly changing data, a range of case fatality ratio estimates for coronavirus disease 2019 (COVID-19) have been produced that differ substantially in magnitude. We aimed to provide robust estimates, accounting for censoring and ascertainment biases. Methods We collected individual-case data for patients who died from COVID-19 in Hubei, mainland China (reported by national and provincial health commissions to Feb 8, 2020), and for cases outside of mainland China (from government or ministry of health websites and media reports for 37 countries, as well as Hong Kong and Macau, until Feb 25, 2020). These individual-case data were used to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the case fatality ratio by relating the aggregate distribution of cases to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for demography and age-based and location-based under-ascertainment. We also estimated the case fatality ratio from individual line-list data on 1334 cases identified outside of mainland China. Using data on the prevalence of PCR-confirmed cases in international residents repatriated from China, we obtained age-stratified estimates of the infection fatality ratio. Furthermore, data on age-stratified severity in a subset of 3665 cases from China were used to estimate the proportion of infected individuals who are likely to require hospitalisation. Findings Using data on 24 deaths that occurred in mainland China and 165 recoveries outside of China, we estimated the mean duration from onset of symptoms to death to be 17·8 days (95% credible interval [CrI] 16·9–19·2) and to hospital discharge to be 24·7 days (22·9–28·1). In all laboratory confirmed and clinically diagnosed cases from mainland China (n=70 117), we estimated a crude case fatality ratio (adjusted for censoring) of 3·67% (95% CrI 3·56–3·80). However, after further adjusting for demography and under-ascertainment, we obtained a best estimate of the case fatality ratio in China of 1·38% (1·23–1·53), with substantially higher ratios in older age groups (0·32% [0·27–0·38] in those aged <60 years vs 6·4% [5·7–7·2] in those aged ≥60 years), up to 13·4% (11·2–15·9) in those aged 80 years or older. Estimates of case fatality ratio from international cases stratified by age were consistent with those from China (parametric estimate 1·4% [0·4–3·5] in those aged <60 years [n=360] and 4·5% [1·8–11·1] in those aged ≥60 years [n=151]). Our estimated overall infection fatality ratio for China was 0·66% (0·39–1·33), with an increasing profile with age. Similarly, estimates of the proportion of infected individuals likely to be hospitalised increased with age up to a maximum of 18·4% (11·0–7·6) in those aged 80 years or older. Interpretation These early estimates give an indication of the fatality ratio across the spectrum of COVID-19 disease and show a strong age gradient in risk of death. Funding UK Medical Research Council.
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              Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study

              Summary Background Since December, 2019, an outbreak of coronavirus disease 2019 (COVID-19) has spread globally. Little is known about the epidemiological and clinical features of paediatric patients with COVID-19. Methods We retrospectively retrieved data for paediatric patients (aged 0–16 years) with confirmed COVID-19 from electronic medical records in three hospitals in Zhejiang, China. We recorded patients' epidemiological and clinical features. Findings From Jan 17 to March 1, 2020, 36 children (mean age 8·3 [SD 3·5] years) were identified to be infected with severe acute respiratory syndrome coronavirus 2. The route of transmission was by close contact with family members (32 [89%]) or a history of exposure to the epidemic area (12 [33%]); eight (22%) patients had both exposures. 19 (53%) patients had moderate clinical type with pneumonia; 17 (47%) had mild clinical type and either were asymptomatic (ten [28%]) or had acute upper respiratory symptoms (seven [19%]). Common symptoms on admission were fever (13 [36%]) and dry cough (seven [19%]). Of those with fever, four (11%) had a body temperature of 38·5°C or higher, and nine (25%) had a body temperature of 37·5–38·5°C. Typical abnormal laboratory findings were elevated creatine kinase MB (11 [31%]), decreased lymphocytes (11 [31%]), leucopenia (seven [19%]), and elevated procalcitonin (six [17%]). Besides radiographic presentations, variables that were associated significantly with severity of COVID-19 were decreased lymphocytes, elevated body temperature, and high levels of procalcitonin, D-dimer, and creatine kinase MB. All children received interferon alfa by aerosolisation twice a day, 14 (39%) received lopinavir–ritonavir syrup twice a day, and six (17%) needed oxygen inhalation. Mean time in hospital was 14 (SD 3) days. By Feb 28, 2020, all patients were cured. Interpretation Although all paediatric patients in our cohort had mild or moderate type of COVID-19, the large proportion of asymptomatic children indicates the difficulty in identifying paediatric patients who do not have clear epidemiological information, leading to a dangerous situation in community-acquired infections. Funding Ningbo Clinical Research Center for Children's Health and Diseases, Ningbo Reproductive Medicine Centre, and Key Scientific and Technological Innovation Projects of Wenzhou.
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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
                13 May 2020
                13 May 2020
                Affiliations
                [a ]Department of Nephrology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK
                [b ]Division of Pediatric Nephrology, Heidelberg University Hospital, Heidelberg, Germany
                [c ]Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
                [d ]Pediatric Nephrology, Hannover Medical School, Hannover, Germany
                Article
                S2352-4642(20)30145-0
                10.1016/S2352-4642(20)30145-0
                7220160
                32411815
                26361080-b610-4fc0-b226-ba340adbbb89
                © 2020 Elsevier Ltd. All rights reserved.

                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.

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