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      Clinical and virological data of the first cases of COVID-19 in Europe: a case series

      , Prof, MD a , g , , , Prof, MD b , g , , , MD h , k , , MD a , , MD b , g , , PharmD i , , PharmD l , m , , PharmD l , m , , MSc i , , PhD c , g , , PhD i , j , , PharmD c , , PharmD l , m , , PhD n , , Prof, MD d , g , , Prof, PhD e , g , , Prof, MD f , g , , Prof, MD c , g , , Prof, MD h , k , , Prof, MD b , g , , Prof, MD l , m , , , Prof, PhD i , , , Prof, MD a , g , , *

      The Lancet. Infectious Diseases

      Elsevier Ltd.

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          Summary

          Background

          On Dec 31, 2019, China reported a cluster of cases of pneumonia in people at Wuhan, Hubei Province. The responsible pathogen is a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the relevant features of the first cases in Europe of confirmed infection, named coronavirus disease 2019 (COVID-19), with the first patient diagnosed with the disease on Jan 24, 2020.

          Methods

          In this case series, we followed five patients admitted to Bichat-Claude Bernard University Hospital (Paris, France) and Pellegrin University Hospital (Bordeaux, France) and diagnosed with COVID-19 by semi-quantitative RT-PCR on nasopharyngeal swabs. We assessed patterns of clinical disease and viral load from different samples (nasopharyngeal and blood, urine, and stool samples), which were obtained once daily for 3 days from hospital admission, and once every 2 or 3 days until patient discharge. All samples were refrigerated and shipped to laboratories in the National Reference Center for Respiratory Viruses (The Institut Pasteur, Paris, and Hospices Civils de Lyon, Lyon, France), where RNA extraction, real-time RT-PCR, and virus isolation and titration procedures were done.

          Findings

          The patients were three men (aged 31 years, 48 years, and 80 years) and two women (aged 30 years and 46 years), all of Chinese origin, who had travelled to France from China around mid-January, 2020. Three different clinical evolutions are described: (1) two paucisymptomatic women diagnosed within a day of exhibiting symptoms, with high nasopharyngeal titres of SARS-CoV-2 within the first 24 h of the illness onset (5·2 and 7·4 log 10 copies per 1000 cells, respectively) and viral RNA detection in stools; (2) a two-step disease progression in two young men, with a secondary worsening around 10 days after disease onset despite a decreasing viral load in nasopharyngeal samples; and (3) an 80-year-old man with a rapid evolution towards multiple organ failure and a persistent high viral load in lower and upper respiratory tract with systemic virus dissemination and virus detection in plasma. The 80-year-old patient died on day 14 of illness (Feb 14, 2020); all other patients had recovered and been discharged by Feb 19, 2020.

          Interpretation

          We illustrated three different clinical and biological types of evolution in five patients infected with SARS-CoV-2 with detailed and comprehensive viral sampling strategy. We believe that these findings will contribute to a better understanding of the natural history of the disease and will contribute to advances in the implementation of more efficient infection control strategies.

          Funding

          REACTing (Research & Action Emerging Infectious Diseases).

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          Most cited references 8

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission

            Summary Background Human infection with a novel coronavirus named Middle East Respiratory Syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia and the Middle East in September, 2012, with 44 laboratory-confirmed cases as of May 23, 2013. We report detailed clinical and virological data for two related cases of MERS-CoV disease, after nosocomial transmission of the virus from one patient to another in a French hospital. Methods Patient 1 visited Dubai in April, 2013; patient 2 lives in France and did not travel abroad. Both patients had underlying immunosuppressive disorders. We tested specimens from the upper (nasopharyngeal swabs) or the lower (bronchoalveolar lavage, sputum) respiratory tract and whole blood, plasma, and serum specimens for MERS-CoV by real-time RT-PCR targeting the upE and Orf1A genes of MERS-CoV. Findings Initial clinical presentation included fever, chills, and myalgia in both patients, and for patient 1, diarrhoea. Respiratory symptoms rapidly became predominant with acute respiratory failure leading to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Both patients developed acute renal failure. MERS-CoV was detected in lower respiratory tract specimens with high viral load (eg, cycle threshold [Ct] values of 22·9 for upE and 24 for Orf1a for a bronchoalveolar lavage sample from patient 1; Ct values of 22·5 for upE and 23·9 for Orf1a for an induced sputum sample from patient 2), whereas nasopharyngeal specimens were weakly positive or inconclusive. The two patients shared the same room for 3 days. The incubation period was estimated at 9–12 days for the second case. No secondary transmission was documented in hospital staff despite the absence of specific protective measures before the diagnosis of MERS-CoV was suspected. Patient 1 died on May 28, due to refractory multiple organ failure. Interpretation Patients with respiratory symptoms returning from the Middle East or exposed to a confirmed case should be isolated and investigated for MERS-CoV with lower respiratory tract sample analysis and an assumed incubation period of 12 days. Immunosuppression should also be taken into account as a risk factor. Funding French Institute for Public Health Surveillance, ANR grant Labex Integrative Biology of Emerging Infectious Diseases, and the European Community's Seventh Framework Programme projects EMPERIE and PREDEMICS.
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              Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome

              Summary Severe acute respiratory syndrome (SARS) is thought to be caused by a novel coronavirus, SARS-associated coronavirus. We studied viral shedding of SARS coronavirus to improve diagnosis and infection control. Reverse-transcriptase PCR was done on 2134 specimens of different types. 355 (45%) specimens of nasopharyngeal aspirates and 150 (28%) of faeces were positive for SARS coronavirus RNA. Positive rates peaked at 6–11 days after onset of illness for nasopharyngeal aspirates (87 of 149 [58%], to 37 of 62 [60%]), and 9–14 days for faeces (15 of 22 [68%], to 26 of 37 [70%]). Overall, peak viral loads were reached at 12–14 days of illness when patients were probably in hospital care, which would explain why hospital workers were prone to infection. Low rate of viral shedding in the first few days of illness meant that early isolation measures would probably be effective.
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                Author and article information

                Contributors
                Journal
                Lancet Infect Dis
                Lancet Infect Dis
                The Lancet. Infectious Diseases
                Elsevier Ltd.
                1473-3099
                1474-4457
                27 March 2020
                27 March 2020
                Affiliations
                [a ]Department of Infectious and Tropical Diseases, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France
                [b ]Medical and Infectious Diseases Intensive Care Unit, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France
                [c ]Department of Virology, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France
                [d ]Infection Control Unit, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France
                [e ]Department of Epidemiology, Biostatistics and Clinical Research, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France
                [f ]Center for Clinical Investigation, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France
                [g ]Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France
                [h ]Department of Infectious Diseases and Tropical Medicine, University Hospital of Bordeaux, Bordeaux, France
                [i ]National Reference Center for Respiratory Viruses, Molecular Genetics of RNA Viruses, CNRS—UMR 3569, The Institut Pasteur, Paris, France
                [j ]Mutualized Platform of Microbiology, Pasteur International Bioresources Network, The Institut Pasteur, Paris, France
                [k ]INSERM U1219, University of Bordeaux, Bordeaux, France
                [l ]National Reference Center for Respiratory Viruses, Department of Virology, Infective Agents Institute, North Hospital Network, Lyon, France
                [m ]Virpath Laboratory, International Center of Research in Infectiology, INSERM U1111, CNRS—UMR 5308, École Normale Supérieure de Lyon, Université Claude Bernard Lyon, Lyon University, Lyon, France
                [n ]Santé Publique France, Saint Maurice, France
                Author notes
                [* ]Correspondence to: Prof Yazdan Yazdanpanah, Department of Infectious and Tropical Diseases, Assistance Publique—Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, 75018 Paris, France yazdan.yazdanpanah@ 123456aphp.fr
                [†]

                Contributed equally

                Article
                S1473-3099(20)30200-0
                10.1016/S1473-3099(20)30200-0
                7156120
                32224310
                © 2020 Elsevier Ltd. All rights reserved.

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                Infectious disease & Microbiology

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