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Viral and Host Factors Related to the Clinic Outcome of the SARS-Cov-2 Infection

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Viral and Host Factors Related to the Clinic Outcome of the SARS-Cov-2 Infection Viral and host factors related to the clinic outcome of the SARS-CoV-2 infection Xiaonan Zhang Shanghai Public Health Clinical Center, Fudan University Yun Tan National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Yun Ling Shanghai Public Health Clinical Center, Fudan University Gang Lu National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Feng Liu National Research Center for Translational Medicine (Shanghai) and State Key Laboratory of Medical Genomics, Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Zhigang Yi Shanghai Public Health Clinical Center and Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University Xiaofang Jia Shanghai Public Health Clinical Center, Fudan University Min Wu Shanghai Public Health Clinical Center, Fudan University Bisheng Shi Shanghai Public Health Clinical Center, Fudan University Shuibao Xu Shanghai Public Health Clinical Center, Fudan University Jun Chen Shanghai Public Health Clinical Center, Fudan University Wei Wang Shanghai Public Health Clinical Center, Fudan University Bing Chen Shanghai Institute of Hematology, Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Lu Jiang Page 1/18 National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Shuting Yu National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Jing Lu Shanghai Institute of Hematology, Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Jingzheng Wang National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Mingzhu Xu Shanghai Public Health Clinical Center, Fudan University Zhenghong Yuan Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University Qin Zhang Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine Xinxin Zhang Research Laboratory of Clinical Virology, Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Guoping Zhao Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences Shengyue Wang ( [email protected] ) National Research Center for Translational Medicine (Shanghai) and State Key Laboratory of Medical Genomics, Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Saijuan Chen ( [email protected] ) National Research Center for Translational Medicine (Shanghai) and State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Aliated to Shanghai Jiao Tong University School of Medicine Hongzhou Lu ( [email protected] ) Shanghai Public Health Clinical Center, Fudan University Research Article Keywords: COVID-19, Genomic sequences, clinical outcomes, virulence Posted Date: March 25th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-19344/v1 Page 2/18 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on May 20th, 2020. See the published version at https://doi.org/10.1038/s41586-020-2355-0. Page 3/18 Abstract At least three months have been passed since the outbreak of the severe acute respiratory disease, COVID-19 in Wuhan city, China in December 2019, caused by the infection of a novel coronavirus, SARS- CoV-2.1,2. Due to its rapid spread throughout China and abroad, knowledge sharing for both its epidemiology and clinic manifestations is urgently need. Here we analyzed the clinical, molecular and immunological data from 326 conrmed cases of SARS-CoV-2 infection in Shanghai. Genomic sequences assembled from 112 quality samples together with uploaded sequences in Global Initiative on Sharing All Inuenza Data (GISAID) showed a stable evolution and suggested two major lineages with differential exposure history during the earliest outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially the reduced CD4+ and CD8+ T cell counts upon admission, was predictive of disease progression. High level of IL-6 and IL-8 during treatment was observed in severe and critical patients and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such age, lymphocytopenia and its associated cytokine storm whereas viral genetic variation did not signicantly affect the outcomes. This comprehensive analysis on the molecular, immunological and clinical data provides a panorama of the key determinants related to the disease outcomes which should be helpful for improving the current combat against this extremely aggressive pandemic. Authors Xiaonan Zhang, Yun Tan, Yun Ling, Gang Lu, Feng Liu, and Zhigang Yi contributed equally to this work. Introduction In December 2019, an outbreak of infectious pneumonia emerged in Wuhan with a strong link to contacts with a seafood market (Huanan Seafood Wholesale Market, HSWM). The causal agent was soon identied to be a novel betacoronavirus sharing around 85% identity with SARS-CoV (severe acute respiratory syndrome coronavirus)1,2, hence named SARS-CoV–2. The genome sequence of SARS-CoV–2 is closest to a bat coronavirus RaTG131. Additional studies revealed high sequence similarity with two pangolin coronaviruses especially in the receptor binding domain3–5. The SARS-CoV–2 caused disease was later ocially named coronavirus disease 19 (COVID–19). On March 11, the World Health Organization has formally declared COVID–19 a world pandemic underscoring the gravity of the current situation6. As of March 13, there have been over 133,000 laboratory conrmed cases of COVID–19 around the globe. In this ongoing epidemic, public health concerns and the urgent need for effective therapeutic and intervention measures require a deep understanding of its epidemiology, transmissibility and pathogenesis. In the last two decades, zoonotic coronaviruses have caused two large-scale outbreaks, i.e. SARS7,8 and MERS9 (Middle East respiratory syndrome) by crossing inter-species barrier. However, the scale of the current SARS-CoV–2 outbreak has overwhelmingly surpassed the previous two. During the SARS and MERS epidemics, continued monitoring of viral genomes from various geographical regions and different Page 4/18 phases of the outbreak was instrumental for understanding the source, evolution and spread of the diseases. In contrast, although HSWM is widely believed to be the birthplace of SARS-CoV–2, in the initial phase of the outbreak (December 2019), there were signicant number of cases (before Jan 1, 2020) who did not have contact with this market10. This raises doubt on its singular origin. Second, the question that whether SARS-CoV–2 has evolved leading to altered virulence during the spread of the disease remains to be answered with additional molecular epidemiological data. Thirdly, although SARS-CoV–2 infection can cause life-threatening respiratory disease, a majority of infected cases manifested mild pneumonia11. The underlying viral and host factors associated with disease outcome are yet to be fully characterized. In this study, we systematically analyzed key immunological parameters spanning the course of infection and obtained viral genomes directly from clinical samples in order to delineate key factors associated with prognosis and to monitor epidemiological feature of the epidemic. Results Overview of the enrollment A total of 326 patients, who were tested positive for SARS-CoV–2 RNA and were admitted into Shanghai Public Health Clinical Center from Jan 20th to Feb 25th, which was the designated hospital receiving all the COVID–19 cases in Shanghai, were included in this study. Their basic clinical and epidemiological information were shown in Extended Data Table 1. The median age of the patients was 51 years (range 15–88) with a male: female sex ratio of 1.10. Among them, 90 were residents of Hubei province coming to Shanghai. 80 were Shanghai residents who had recently been to Hubei province, 52 contacted people from Hubei and 104 had unidentiable exposures. Four categories of infected cases were dened: Five individuals were asymptomatic as having no obvious fever, respiratory symptoms or radiological manifestations (asymptomatic cases). A majority of the patients, 292 patients had mild disease with fever and radiological manifestations of pneumonia(mild cases). There were 12 patients with severe symptoms of dyspnea (respiratory rate >30/min) and signs of expanding ground-glass opacity in the lung within 24–48 hours and were dened as severe cases (severe case). Another 17 patients deteriorated into acute respiratory distress syndrome (ARDS) and required mechanical ventilation or extracorporeal membrane oxygenation (ECMO) and and thus, were categorized as critical (Extended Data Table 1). As of March 13, 308 patients had been discharged, three had deceased (fatality rate 1.14%). The most common comorbidities were hypertension (76 cases), diabetes (24 cases), coronary heart disease (13 cases), chronic hepatitis B (10 cases), chronic obstructive pulmonary disease (2 cases), chronic renal disease (2 cases) and cancer (3 cases). Nucleotide variation in viral genomes
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