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      Sars-Cov-2: Underestimated damage to nervous system

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          Abstract

          Dear Editor, Coronaviruses (CoVs) are large enveloped positive-stranded RNA viruses, which generally induce enteric and respiratory diseases in animals and humans [1]. Novel coronavirus pneumonia (NCP, also called COVID-19) emerged in December 2019 in Wuhan, China [1]. This novel CoV(SARS-CoV-2) has caused a national outbreak of severe pneumonia in China, and rapidly spreads around the world. On March 4, gene sequencing confirmed the presence of SARS-CoV-2 in the cerebrospinal fluid of a 56-year-old patient with NCP in Beijing Ditan Hospital. The patient was diagnosed with viral encephalitis, and the patient's central nervous system was attacked by SARS-CoV-2. This indicates that SARS-CoV-2 can directly invade the nervous system of patients, instead of injuring the nervous system through the immune response to SARS-CoV-2. This is the first evidence that SARS-CoV-2 has directly invaded the nervous system. Genomic analysis shows that SARS-CoV-2 is in the same Betacoronavirus clade as MERS-CoV and SARS-CoV, and shares highly homological sequence with SARS-CoV [1]. The public evidence shows that COVID-19 shares similar pathogenesis with the pneumonia induced by SARS-CoV or MERS-CoV [2]. Moreover, the entry of SARS-CoV-2 into human host cells has been identified to use the same receptor as SARS-CoV [1]. Previous studies have shown that SARS-CoV and MERS-CoV possess neuroinvasive properties, which can be detected in human brains. CoVs may enter the CNS through two distinct routes: hematogenous dissemination or neuronal retrograde dissemination. I think that the way of neuronal retrograde dissemination is more worrying. HCoV-OC43 RNA, a kind of human coronaviruses, could be detected for at least a year in the CNS of infected mice that survived the virus-induced acute encephalitis [3]. Therefore, an apparently innocuous human respiratory pathogen may persist in the human CNS as a component of the brain, like herpes simplex virus (HSV) in a large proportion of the population. If SARS-CoV-2 exists for a long time, like HSV, and it will recur again in predisposed individuals. In addition, the presence of HCoV-229E and HCoV-OC43 was detected in various neurological diseases in humans, including multiple sclerosis (MS) [4]. Multiple sclerosis truly represents a human neurological disease where an infectious agent or agents may play a triggering role, with viruses the most likely culprit in genetically predisposed individuals [5].If the SARS-CoV-2 is latent in CNS for a long time, will the cured patients reappear with neurological diseases because of the latentness of the SARS-CoV-2, which is a doubt for the late neurological complications of the cured patients. If the SARS-CoV-2 is latent in the nervous system for a long period of time, will the cured patients reappear with neurological diseases? This is a question for the cured patients. It is worthy of our further discovery and exploration. In addition, we should also be aware of this problem in further clinical work, strengthen the alertness of clinicians, and jointly solve this problem. Declaration of competing interest The authors declare that they have no conflicts of interest.

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          From SARS to MERS, Thrusting Coronaviruses into the Spotlight

          Coronaviruses (CoVs) have formerly been regarded as relatively harmless respiratory pathogens to humans. However, two outbreaks of severe respiratory tract infection, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), as a result of zoonotic CoVs crossing the species barrier, caused high pathogenicity and mortality rates in human populations. This brought CoVs global attention and highlighted the importance of controlling infectious pathogens at international borders. In this review, we focus on our current understanding of the epidemiology, pathogenesis, prevention, and treatment of SARS-CoV and MERS-CoV, as well as provides details on the pivotal structure and function of the spike proteins (S proteins) on the surface of each of these viruses. For building up more suitable animal models, we compare the current animal models recapitulating pathogenesis and summarize the potential role of host receptors contributing to diverse host affinity in various species. We outline the research still needed to fully elucidate the pathogenic mechanism of these viruses, to construct reproducible animal models, and ultimately develop countermeasures to conquer not only SARS-CoV and MERS-CoV, but also these emerging coronaviral diseases.
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            Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice

            The notion that an infectious respiratory pathogen can damage the central nervous system (CNS) and lead to neurological disease was tested using a human respiratory coronavirus, the OC43 strain of human coronavirus (HCoV-OC43). First, primary cell cultures were used to determine the susceptibility of each type of neural cells to virus infection. Neurons were the target cells, undergoing degeneration during infection, in part due to apoptosis. Second, neuropathogenicity was investigated in susceptible mice. Intracerebral inoculation of HCoV-OC43 into BALB/c mice led to an acute encephalitis with neuronal cell death by necrosis and apoptosis. Infectious virus was apparently cleared from surviving animals, whereas viral RNA persisted for several months. Some of the animals surviving to acute encephalitis presented an abnormal limb clasping reflex and a decrease in motor activity starting several months post-infection. These results suggest that viral persistence could be associated with an increased neuronal degeneration leading to neuropathology and motor deficits in susceptible individuals.
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              Clinical characteristics of laboratory confirmed positive cases of SARS-CoV-2 infection in Wuhan, China: A retrospective single center analysis

              Dear Editor According to the Health Commission of Hubei province, China, multiple pneumonia cases first appeared in Wuhan with unclear etiology in December 2019 [1,2]. Soon after, a novel type of coronavirus SARS-CoV-2 (coronavirus disease 2019; previously 2019‐nCoV) was isolated by Chinese authorities on 7 January 2020 [3,4]. It was reported that in most cases, patients were exposed to the Huanan Seafood Wholesale Market in Wuhan, China, and transmission appeared to be from animals into human [2,5,6]. No province in China has been exempt from the reach of the SARS-CoV-2, and 24 countries have reported cases of the infection until 1st February 2020. To make explicit the pathogenesis and pathophysiology of SARS-CoV-2, we retrospectively analyzed a cohort of patients who were diagnosed with “2019 novel coronavirus disease (COVID-19)” in the Zhongnan Hospital of Wuhan University, describing the clinical features of laboratory-confirmed cases of SARS-CoV-2 infection. (see Table 1 ) Table 1 Demographical and clinical Information, initial outcomes of laboratory tests, management and treatment of 34 patients who were confirmed as being infected with SARS-CoV-2 after admission to Zhongnan Hospital. Table 1 Covariate Level Number % Age, years 56.24 ± 17.14 younger than or equal to 40 8 23.5 41–57 10 29.5 58–69 8 23.5 older than or equal to 70 8 23.5 Sex Female 20 58.8 Male 14 41.2 Comorbidity None 18 52.9 Yes 16 47.1  Diabetes 4 11.8  Hypertension 8 23.5  Cardiovascular disease 6 17.6  Chronic obstructive 1 2.9  pulmonary disease 2 5.9  Malignancy 3 8.8  Chronic liver disease 1 2.9  Hyperuricemia 1 2.9  Hypothyroidism 2 5.9  HIV infection 2 5.9 Symptoms when admitted to the hospital Fever 32 94.1  Temperature of the admission, °C 37.34 ± 0.92  Highest temperature, °C 38.61 ± 0.81 Cough 17 50.0 Myalgia or fatigue 22 64.7 Sputum production 8 23.5 Headache 2 5.9 Diarrhea 5 14.7 Dyspnea 5 14.7 Bilateral involvement of chest radiographs Bilateral 27 79.4 Unilateral 3 8.8 Nothing abnormal detected 1 2.9 Unknown 3 8.8 White blood cell count  Decreased 6 17.6  Increased 4 11.8 Neutrophil count  Increased 4 11.8 Lymphocyte count  Decreased 17 50.0 Hemoglobin  Decreased 13 38.2 Platelet count  Decreased 9 26.5 Prothrombin time  Decreased 1 2.9  Increased 17 50.0 D-dimer  Increased 5 14.7 Albumin  Decreased 25 73.5 Alanine aminotransferase  Increased 8 23.5 Aspartate aminotransferase  Increased 7 20.6 Total bilirubin  Increased 3 8.8 Potassium  Decreased 4 11.8  Increased 2 5.9 Creatinine  Decreased 7 20.6  Increased 6 17.6 Creatine kinase  Increased 1/12 8.3 Myoglobin  Increased 3/12 25.0 Hypersensitive troponin I  Increased 1/15 6.7 Procalcitonin  Increased 13/31 41.9 Erythrocyte sedimentation rate (ESR)  Increased 13/22 59.1 Interleukin  Increased 9/9 100.0 Brain natriuretic peptide (BNP)  Increased 1/4 25.0 Hospitalization ICU care 8 23.5 No-ICU care 26 76.5 Treatment Antibiotic therapy 31 91.2 Antiviral therapy (other drugs but not lopinavir/ritonavir) 32 94.1 Antiviral therapy (switch to lopinavir/ritonavir later) 9 26.5 Use of corticosteroid 21 61.8 Oxygen Support Oxygen Therapy 25 73.5 Non-invasive ventilation or high-flow nasal cannula 2 5.9 Invasive mechanical ventilation 3 8.8 Unknown 4 11.8 Change of chest radiographs (before switching to lopinavir/ritonavir) Worse manifestations 14/16 87.5 Improve manifestations 1/16 6.25 No difference 1/16 6.25 Intervals of re-examined, days 4.5 (3.0–6.0) Unknown 18 52.9 Change of chest radiographs (Refer in particular to the 9 patients who switched to lopinavir/ritonavir later) Improve manifestations 1/9 11.1 Intervals of re-examined, days 4 Not re-examined 8 88.9 Change of Procalcitonin Elevated 4/11 36.4 Declined 3/11 27.3 No difference 4/11 36.4 Unknown 23 67.6 Prognosis Hospitalization 33 97.1 Home isolation 1 2.9 This retrospective study was approved by the Zhongnan Hospital of Wuhan University's ethical review board (Clinical Ethical Approval No.2020015). In total, the information of 84 patients who were diagnosed from December 2019 to January 2020 were collected and patients who did not undergo laboratory confirmation of SARS-CoV-2 or who were tested negative in the laboratory of Zhongnan Hospital were excluded in this research. Ultimately, 34 patients who tested positive to the SARS-CoV-2 at least once via laboratory were included in this study. Among these 34 patients, the earliest admission date was 21 December 2019 and the latest admission date was 28 January 2020. Patients were followed up to 29 January 2020, any missing data was recorded as unknown. Demographical, clinical, laboratory and imaging tests (including CT and X-ray) data as well as management, treatment, and prognosis for the included patients were acquired from their medical history. Data collected were sorted and summarized. The mean age of those patients was approximately 56 years and the range of age is from 26 to 88 years old. There were 8 patients who were younger than 40 years of age and also 8 patients who were older than or equal to 70 years of age. We didn't obtain young patients in our cohort and further research are needed to verify whether children and juvenile are of less likely to be infected. The number of female patients was 20, accounting for 58.8% of all these 34 patients. Most patients (64.7%) lived in the Wuchang district. Among the patients, 47.1% had underlying diseases including diabetes, hypertension, cardiovascular disease, chronic obstructive, pulmonary disease, malignancy, chronic liver disease, hyperuricemia and hypothyroidism. Two patients were known to be human immunodeficiency virus (HIV) positive. Up to 94.1% patients had fever on admission or during hospitalization. The highest recorded temperature during hospitalization was 38.61 °C (±0.81 °C). Half of the patients had coughs, and nearly two thirds of patients had myalgia or fatigue. A small group of patients had symptoms of diarrhea and headache. It is worth noting that a fraction of patients did not present with fever. Their symptoms were mild and limited to coughing and fatigue. In addition, findings from the chest radiographs indicated that up to 79.4% patients were infiltrated bilaterally. Only 3 patients showed unilateral infiltrates in their chest radiographs. Surprisingly, one patient presented normally in chest radiographs and this patient only presented with fever and fatigue. These variations in presentations may lead to a missed diagnosis in the primary examination. Therefore, clinicians must be mindful of patients presenting with atypical symptoms since the appearance of pulmonary infiltrates may be delayed and the absence of pulmonary changes on initial imaging does not mean that pneumonia will not develop. 17.6% patients presented with leucopenia, while 11.8% patients presented with leukocytosis, on admission. It is worth noting that up to half of the patients had lymphopenia and 73% showed hypoalbuminemia. Most patients had a reduction in hemoglobin (38.2%) and prolonged prothrombin time (50%). Sodium level of all the patients was within the normal range. Most patients (52.9%) had normal serum levels of procalcitonin. Interleukin-6 level was tested in only 9 patients, and all 9 patients showed an increased level of Interleukin-6. Erythrocyte sedimentation rate (ESR) also increased in most cases (59.1%). Only one out of four patients who were tested, showed elevated brain natriuretic peptide. Among patients who had multiple laboratory confirmation tests, 2 patients changed from positive to negative, while 3 patients changed from negative to positive. Of the 34 patients, 8 (23.5%) were initially or subsequently admitted to the intensive care unit (ICU) and all of them were over 50 years-old. Over 90% of patients received antibiotic therapy, while only 26.5% used corticosteroid. Up to 94.1% patients received antiviral therapy other than lopinavir/ritonavir. Of these, 9 patients switched to lopinavir/ritonavir after a period of time. Patients who were not prescribed lopinavir/ritonavir and patients prior to being prescribed lopinavir/ritonavir tended to have worse manifestations on their chest radiographs (14 out of 16, 87.5%). The intervals between examinations were 4.5 days. Surprisingly, one patient who was prescribed lopinavir/ritonavir at a later date, and who was re-examined after using lopinavir/ritonavir for four days, showed improvements in his chest radiographs. Even he was worse according to the changes of CT before switching to lopinavir/ritonavir therapy. However, as other patients were not re-examined, more information relating to the effects of lopinavir/ritonavir therapy could not be determined and further investigation and evaluation are needed. As for procalcitonin, of the 11 patients who received re-examination, 4 showed an elevation of procalcitonin, while 3 patients showed the opposite. Only one patient out of the 34 patients was treated with home isolation. All other patients required hospitalization. In summary, the range of age in these cohort is from 26 to 88 years old and the mean age is approximately 56 years old. Patients infected with SARS-CoV-2 were more likely to present with lymphopenia, and increase of ESR and IL-6. Since there are patients with atypical symptoms and imaging of chest radiograph, more attention to atypical symptoms during the early stage of COVID-19 and repeated chest imaging examinations are called for. Funding This research received no external funding. CRediT authorship contribution statement Yihui Huang: Conceptualization, Writing - original draft. Mengqi Tu: Software. Shipei Wang: Conceptualization. Sichao Chen: Methodology. Wei Zhou: Resources. Danyang Chen: Validation. Lin Zhou: Formal analysis. Min Wang: Investigation. Yan Zhao: Validation. Wen Zeng: Data curation. Qi Huang: Visualization. Hai'bo Xu: Investigation. Zeming Liu: Writing - original draft. Liang Guo: Supervision, Project administration. Declaration of competing interest The authors declare no conflict of interest.
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                Author and article information

                Contributors
                Journal
                Travel Med Infect Dis
                Travel Med Infect Dis
                Travel Medicine and Infectious Disease
                Elsevier Ltd.
                1477-8939
                1873-0442
                24 March 2020
                24 March 2020
                : 101642
                Affiliations
                [1]Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
                [2]Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
                [3]Department of Rheumatology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
                [4]Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
                Author notes
                []Corresponding author. sunshinezlyjg@ 123456163.com
                [1]

                These authors contributed to this work equally and should be regarded as co-first authors.

                Article
                S1477-8939(20)30110-1 101642
                10.1016/j.tmaid.2020.101642
                7269702
                32220634
                fdf2c35d-700c-4dd2-9ba9-5e198d056439
                © 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.

                History
                : 9 March 2020
                : 18 March 2020
                : 20 March 2020
                Categories
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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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