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      High mortality among kidney transplant recipients diagnosed with coronavirus disease 2019: Results from the Brazilian multicenter cohort study

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      1 , 2 , 3 , * , 4 , 5 , 6 , 2 , 2 , 7 , 8 , 5 , 6 , 9 , 3 , 10 , 11 , 12 , 13 , 14 , 15 , 7 , 16 , 17 , 18 , 1 , 2 , 1 , 2 , on behalf of COVID-19-KT Brazil
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          Abstract

          Background

          Kidney transplant (KT) recipients are considered a high-risk group for unfavorable outcomes in the course of coronavirus disease 2019 (COVID-19).

          Aim

          To describe the clinical aspects and outcomes of COVID-19 among KT recipients.

          Methods

          This multicenter cohort study enrolled 1,680 KT recipients diagnosed with COVID-19 between March and November 2020, from 35 Brazilian centers. The main outcome was the 90-day cumulative incidence of death, for the entire cohort and according to acute kidney injury (AKI) and renal replacement therapy (RRT) requirement. Fatality rates were analyzed according to hospitalization, intensive care unit (ICU) admission, and mechanical ventilation (MV) requirement. Multivariable analysis was performed by logistic regression for the probability of hospitalization and death.

          Results

          The median age of the recipients was 51.3 years, 60.4% were men and 11.4% were Afro-Brazilian. Comorbidities were reported in 1,489 (88.6%), and the interval between transplantation and infection was 5.9 years. The most frequent symptoms were cough (54%), myalgia (40%), dyspnea (37%), and diarrhea (31%), whereas the clinical signs were fever (61%) and hypoxemia (13%). Hospitalization was required in 65.1%, and immunosuppressive drugs adjustments were made in 74.4% of in-hospital patients. ICU admission was required in 34.6% and MV in 24.9%. In the multivariable modeling, the variables related with the probability of hospitalization were age, hypertension, previous cardiovascular disease, recent use of high dose of steroid, and fever, dyspnea, diarrhea, and nausea or vomiting as COVID-19 symptoms. On the other hand, the variables that reduced the probability of hospitalization were time of COVID-19 symptoms, and nasal congestion, headache, arthralgia and anosmia as COVID-19 symptoms. The overall 90-day cumulative incidence of death was 21.0%. The fatality rates were 31.6%, 58.2%, and 75.5% in those who were hospitalized, admitted to the ICU, and required MV, respectively. At the time of infection, 23.2% had AKI and 23.4% required RRT in the follow-up. The cumulative incidence of death was significantly higher among recipients with AKI (36.0% vs. 19.1%, P < 0.0001) and in those who required RRT (70.8% vs. 10.1%, P < 0.0001). The variables related with the probability of death within 90 days after COVID-19 were age, time after transplantation, presence of hypertension, previous cardiovascular disease, use of tacrolimus and mycophenolate, recent use of high dose of steroids, and dyspnea as COVID-19 symptom. On the other hand, the variables that reduced the risk of death were time of symptoms, and headache and anosmia as COVID-19 symptoms.

          Conclusion

          The patients diagnosed with COVID-19 were long-term KT recipients and most of them had some comorbidities. One in every five patients died, and the rate of death was significantly higher in those with AKI, mainly when RRT was required.

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          Most cited references33

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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              Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

              Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysis
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 July 2021
                2021
                28 July 2021
                : 16
                : 7
                : e0254822
                Affiliations
                [1 ] Department of Medicine, Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil
                [2 ] Department of Transplantation, Hospital do Rim, Fundação Oswaldo Ramos, São Paulo, SP, Brazil
                [3 ] Renal Transplant Unit, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
                [4 ] Department of Clinical Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
                [5 ] Hospital Universitário Walter Cantídio, Fortaleza, CE, Brazil
                [6 ] Hospital Geral de Fortaleza, Fortaleza, CE, Brazil
                [7 ] Department of Internal Medicine, Universidade Estadual Paulista-UNESP, Botucatu, SP, Brazil
                [8 ] Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
                [9 ] Hospital de Base, Medical School FAMERP, São José do Rio Preto, SP, Brazil
                [10 ] Federal University of Maranhão, São Luiz, MA, Brazil
                [11 ] Hospital de Clínicas de Porto Alegre, Federal Univertisy of Rio Grande do Sul, Porto Alegre, RS, Brazil
                [12 ] Division of Nephrology and Kidney Transplantation, Onofre Lopes University Hospital, Natal, RN, Brazil
                [13 ] Hospital Santa Isabel, Blumenau, SC, Brazil
                [14 ] Division of Nephrology, Renal Transplant Unit, Renal Transplant Research Laboratory, School of Medical Sciences, University of Campinas–UNICAP, Campinas, SP, Brazil
                [15 ] Santa Casa de Misericórdia de Juiz de Fora, Juiz de Fora, MG, Brazil
                [16 ] Hospital Municipal São José (HMSJ), Joinville, SC, Brazil
                [17 ] Division of Nephrology, School of Medicine of Ribeirão Preto, University of Sao Paulo, Ribeirão Preto, SP, Brazil
                [18 ] Hospital Santa Marcelina, São Paulo, SP, Brazil
                Istituto Di Ricerche Farmacologiche Mario Negri, ITALY
                Author notes

                Competing Interests: The present study was partially supported by Novartis Pharma Brazil. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                ‡ Lúcio R. Requião-Moura and Tainá Veras de Sandes-Freitas are Co first authors on this work. Also Helio Tedesco-Silva and José Medina-Pestana are Co senior authors on this work.

                ¶ Membership of the COVID-19-KT Brazil is listed in the Acknowledgments.

                Author information
                https://orcid.org/0000-0001-8751-9048
                https://orcid.org/0000-0002-2795-6681
                https://orcid.org/0000-0002-0280-1069
                Article
                PONE-D-21-05548
                10.1371/journal.pone.0254822
                8318290
                34320005
                4ace8850-7cf6-4a5b-a5f6-9d42a4a82ce7
                © 2021 Requião-Moura et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 February 2021
                : 2 July 2021
                Page count
                Figures: 4, Tables: 5, Pages: 20
                Funding
                Funded by: Novartis Pharma (BR)
                Award ID: There is no a specific number
                Award Recipient :
                The present study was partially supported by Novartis Pharma Brazil. This support was not associated with any relevant declarations relating to employment, consultancy, patents, products in development and marketed products. Novartis Brazil, represented by the Evidence Generation Medical Affairs Pharma Team, established a research collaboration with TVSF to support the execution of the study. This collaboration involved financial support to operational costs with study execution, statistical data analysis, language review and submission fees. In addition, Novartis collaborated with protocol and final study report review, support with the regulatory process review and data cleaning. There was no additional funding received from Novartis Brazil for this study. There was no additional external funding received for this study.
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