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      The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

      review-article
      , DVM a , , , MD b , , , MD c , , MD d , , Prof, PhD e , f , , MD g , i , , Prof, PhD j , k , , Prof, PhD j , k , , Prof, MD l , , Prof, MD l , m , , MD l , n , , MD o , , PhD p , , Prof, DrSc q , , PhD r , , Prof, MD r , , PhD s , , Prof, MD t , , PhD u , v , , MSc u , , Prof, MD w , , MD h , x , , PhD y , , MD y , , PhD z , , Prof, MD t , z , aa , , Prof, MD ab , , MD v , ac , , MD ad , , Prof, MD ae , , Prof, MD p , af , ag , , Prof, MD t , , MD u , v , , PhD l , *
      The Lancet. Respiratory Medicine
      Elsevier Ltd.

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          Abstract

          The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

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          Most cited references263

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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 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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                Author and article information

                Journal
                Lancet Respir Med
                Lancet Respir Med
                The Lancet. Respiratory Medicine
                Elsevier Ltd.
                2213-2600
                2213-2619
                6 May 2021
                6 May 2021
                Affiliations
                [a ]Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
                [b ]Department of Anaesthesiology, University of Göttingen Medical Center, Göttingen, Georg-August University of Göttingen, Göttingen, Germany
                [c ]Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, Warsaw, Poland
                [d ]Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
                [e ]Guy's and St Thomas' NHS Foundation Trust, ICU support offices, St Thomas' Hospital, London, UK
                [f ]School of Immunology & Microbial Sciences, Kings College London, London, UK
                [g ]Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), Charité–Universitätsmedizin Berlin, Berlin, Germany
                [h ]Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany
                [i ]Berlin Institute of Health, Berlin, Germany
                [j ]Hospices Civils de Lyon, Immunology Laboratory, Edouard Herriot Hospital, Lyon, France
                [k ]Pathophysiology of Injury-Induced Immunosuppression, Equipe d'Accueil 7426, Université Claude Bernard Lyon 1 – bioMérieux – Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
                [l ]Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital–Friedrich Schiller University, Jena, Germany
                [m ]Center for Clinical Studies, Jena University Hospital–Friedrich Schiller University, Jena, Germany
                [n ]Institute for Infectious Disease and Infection Control, Jena University Hospital–Friedrich Schiller University, Jena, Germany
                [o ]Pediatric Critical Care Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
                [p ]Department of Intensive Care Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
                [q ]Agence Nationale de la Recherche, Paris, France
                [r ]Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
                [s ]Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Essen, University Duisburg–Essen, Essen, Germany
                [t ]Division of Infectious Diseases and Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
                [u ]Group for Biomedical Research in Sepsis, Hospital Universitario Río Hortega de Valladolid, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain
                [v ]Centro de Investigación Biomedica En Red-Enfermedades Respiratorias, Instituto de salud Carlos III, Madrid, Spain
                [w ]Multidisciplinary Intensive Care Research Organization, St James's Hospital, Dublin, Ireland
                [x ]Department of Immunology, Labor Berlin–Charité Vivantes, Berlin, Germany
                [y ]Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
                [z ]Pneumology Department, Respiratory Institute, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, ICREA, CIBERESUCICOVID, Spain
                [aa ]SGR 911–ICREA Academia, Barcelona, Spain
                [ab ]4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
                [ac ]Intensive Care Department and Shock, Organ Dysfunction and Resuscitation Research Group, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
                [ad ]Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy
                [ae ]Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
                [af ]Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania
                [ag ]Department for Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
                Author notes
                [* ]Correspondence to: Dr Ignacio Rubio, Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
                [†]

                Contributed equally

                Article
                S2213-2600(21)00218-6
                10.1016/S2213-2600(21)00218-6
                8102044
                33965003
                47d3ff3f-a122-49d5-a115-57039fce3983
                © 2021 Elsevier Ltd. All rights reserved.

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