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1.
Viruses ; 12(7), 2020.
Article | WHO COVID | ID: covidwho-662395

ABSTRACT

With the frequent outbreaks of emerging infectious diseases in recent years, an effective broad-spectrum antiviral drug is becoming an urgent need for global public health Cholesterol-25-hydroxylase (CH25H) and its enzymatic products 25-hydroxycholesterol (25HC), a well-known oxysterol that regulates lipid metabolism, have been reported to play multiple functions in modulating cholesterol homeostasis, inflammation, and immune responses CH25H and 25HC were recently identified as exerting broadly antiviral activities, including upon a variety of highly pathogenic viruses such as human immunodeficiency virus (HIV), Ebola virus (EBOV), Nipah virus (NiV), Rift Valley fever virus (RVFV), and Zika virus (ZIKV) The underlying mechanisms for its antiviral activities are being extensively investigated but have not yet been fully clarified In this study, we summarized the current findings on how CH25H and 25HC play multiple roles to modulate cholesterol metabolism, inflammation, immunity, and antiviral infections Overall, 25HC should be further studied as a potential therapeutic agent to control emerging infectious diseases in the future

2.
JAMA Intern Med ; 2020 Sep 10.
Article in English | MEDLINE | ID: covidwho-756227

ABSTRACT

Importance: Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19. Design, Setting and Participants: Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per µL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing. Exposures: Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 µg/kg, subcutaneously at days 0-2). Main Outcomes and Measures: The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score. Results: Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, -13%; 95%CI, -21.4% to -5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/µL vs usual care group median of 620/µL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group. Conclusion and Relevance: In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000030007.

3.
Chinese J. Lab. Med. ; 7(43): 691-696, 20200711.
Article in Chinese | ELSEVIER | ID: covidwho-706041

ABSTRACT

With the gradual progress of epidemic prevention and control work, the process of epidemic prevention and control in COVID-19 has entered a critical period. As the main method to diagnose patients with COVID-19,the disadvantages of nucleic acid detection are gradually revealed. As an important immune response product, specific antibodies have been rapidly applied to the laboratory detection of 2019 novel coronavirus (2019-nCoV), combined with nucleic acid detection for rapid diagnosis and screening of patients with COVID-19. This paper explores and discusses the production pattern and common detection methods of 2019-nCoV specific antibodies and the application and limitations of antibody detection in the clinical work to promote the application and development of specific antibody in COVID-19 diagnosis.

4.
J Virol ; 94(15)2020 07 16.
Article in English | MEDLINE | ID: covidwho-661225

ABSTRACT

The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in a pandemic. Here, we used X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptors allows the definition of residues important for binding. From the 20 amino acids in ACE2 that contact S, up to 7 can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or acquisition of N-glycosylation sites located near the S interface. Of note, pigs and dogs, which are not infected or are not effectively infected and have only a few changes in the binding site, exhibit relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with that from bat coronavirus strain RaTG13 (Bat-CoV-RaTG13) and pangolin coronavirus (Pangolin-CoV) strain hCoV-19/pangolin/Guangdong/1/2019 revealed that the latter contains only one substitution, whereas Bat-CoV-RaTG13 exhibits five. However, ACE2 of pangolin exhibits seven changes relative to human ACE2, and a similar number of substitutions is present in ACE2 of bats, raccoon dogs, and civets, suggesting that SARS-CoV-2 may not be especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-CoV-2.IMPORTANCE SARS-CoV-2 is threatening people worldwide, and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear, and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes, indicating that the species barrier might be low. Exceptions are dogs and especially pigs, which revealed relatively low ACE2 expression levels in the respiratory tract. Monitoring of animals is necessary to prevent the generation of a new coronavirus reservoir. Finally, our analysis also showed that SARS-CoV-2 may not be specifically adapted to any of its putative intermediate hosts.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment , Animals , Animals, Domestic , Betacoronavirus/metabolism , Chiroptera/virology , Coronavirus Infections/metabolism , Dogs , Glycosylation , Host-Pathogen Interactions , Humans , Models, Animal , Pandemics , Pets , Pneumonia, Viral/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Raccoons/virology , Sequence Alignment , Sequence Analysis, Protein , Swine , Viverridae/virology
5.
Non-conventional | WHO COVID | ID: covidwho-637918

ABSTRACT

The COVID-19 pandemic is the most important public health threat in recent history Here we study how its causal agent, SARS-CoV-2, has diversified genetically since its first emergence in December 2019 We have created a pipeline combining both phylogenetic and structural analysis to identify possible human-adaptation related mutations in a data set consisting of 4,894 SARS-CoV-2 complete genome sequences Although the phylogenetic diversity of SARS-CoV-2 is low, the whole genome phylogenetic tree can be divided into five clusters/clades based on the tree topology and clustering of specific mutations, but its branches exhibit low genetic distance and bootstrap support values We also identified 11 residues that are high-frequency substitutions, with four of them currently showing some signal for potential positive selection These fast-evolving sites are in the non-structural proteins nsp2, nsp5 (3CL-protease), nsp6, nsp12 (polymerase) and nsp13 (helicase), in accessory proteins (ORF3a, ORF8) and in the structural proteins N and S Temporal and spatial analysis of these potentially adaptive mutations revealed that the incidence of some of these sites was declining after having reached an (often local) peak, whereas the frequency of other sites is continually increasing and now exhibit a worldwide distribution Structural analysis revealed that the mutations are located on the surface of the proteins that modulate biochemical properties We speculate that this improves binding to cellular proteins and hence represents fine-tuning of adaptation to human cells Our study has implications for the design of biochemical and clinical experiments to assess whether important properties of SARS-CoV-2 have changed during the epidemic

6.
Chin Med J (Engl) ; 133(12): 1390-1396, 2020 Jun 20.
Article in English | MEDLINE | ID: covidwho-608052

ABSTRACT

BACKGROUND: Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. METHODS: From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. RESULTS: Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. CONCLUSIONS: LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Lung Transplantation/methods , Pneumonia, Viral/complications , Pulmonary Fibrosis/surgery , Respiratory Distress Syndrome, Adult/surgery , Aged , Coronavirus Infections/mortality , Extracorporeal Membrane Oxygenation , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pulmonary Fibrosis/mortality , Respiratory Distress Syndrome, Adult/mortality
7.
Pharmacol Res ; 158: 104850, 2020 08.
Article in English | MEDLINE | ID: covidwho-478027

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread worldwide through person-to-person contact, causing a public health emergency of international concern. At present, there is no specific antiviral treatment recommended for SARS-CoV-2 infection. Liu Shen capsule (LS), a traditional Chinese medicine, has been proven to have a wide spectrum of pharmacological properties, such as anti-inflammatory, antiviral and immunomodulatory activities. However, little is known about the antiviral effect of LS against SARS-CoV-2. Herein, the study was designed to investigate the antiviral activity of SARS-CoV-2 and its potential effect in regulating the host's immune response. The inhibitory effect of LS against SARS-CoV-2 replication in Vero E6 cells was evaluated by using the cytopathic effect (CPE) and plaque reduction assay. The number of virions of SARS-CoV-2 was observed under transmission electron microscope after treatment with LS. Proinflammatory cytokine expression levels upon SARS-CoV-2 infection in Huh-7 cells were measured by real-time quantitative PCR assays. The results showed that LS could significantly inhibit SARS-CoV-2 replication in Vero E6 cells, and reduce the number of virus particles and it could markedly reduce pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-8, CCL-2/MCP-1 and CXCL-10/IP-10) production at the mRNA levels. Moreover, the expression of the key proteins in the NF-κB/MAPK signaling pathway was detected by western blot and it was found that LS could inhibit the expression of p-NF-κB p65, p-IκBα and p-p38 MAPK, while increasing the expression of IκBα. These findings indicate that LS could inhibit SARS-CoV-2 virus infection via downregulating the expression of inflammatory cytokines induced virus and regulating the activity of NF-κB/MAPK signaling pathway in vitro, making its promising candidate treatment for controlling COVID-19 disease.


Subject(s)
Betacoronavirus/drug effects , Complex Mixtures/pharmacology , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Signal Transduction/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/virology , Humans , Inflammation Mediators/metabolism , Pandemics , Pneumonia, Viral/virology , Virion/drug effects
9.
J Infect ; 81(1): e28-e32, 2020 07.
Article in English | MEDLINE | ID: covidwho-46420

ABSTRACT

An outbreak of new coronavirus SARS-CoV-2 was occurred in Wuhan, China and rapidly spread to other cities and nations. The standard diagnostic approach that widely adopted in the clinic is nucleic acid detection by real-time RT-PCR. However, the false-negative rate of the technique is unneglectable and serological methods are urgently warranted. Here, we presented the colloidal gold-based immunochromatographic (ICG) strip targeting viral IgM or IgG antibody and compared it with real-time RT-PCR. The sensitivity of ICG assay with IgM and IgG combinatorial detection in nucleic acid confirmed cases were 11.1%, 92.9% and 96.8% at the early stage (1-7 days after onset), intermediate stage (8-14 days after onset), and late stage (more than 15 days), respectively. The ICG detection capacity in nucleic acid-negative suspected cases was 43.6%. In addition, the concordance of whole blood samples and plasma showed Cohen's kappa value of 0.93, which represented the almost perfect agreement between two types of samples. In conclusion, serological ICG strip assay in detecting SARS-CoV-2 infection is both sensitive and consistent, which is considered as an excellent supplementary approach in clinical application.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Coronavirus Infections/blood , Coronavirus Infections/virology , Immunoassay/methods , Pneumonia, Viral/blood , Pneumonia, Viral/virology , Serologic Tests , Adult , Aged , Aged, 80 and over , Coronavirus Infections/diagnosis , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Young Adult
10.
Clin. Transl. Med. ; 1(10): 161-168, 20200301.
Article in English | ELSEVIER | ID: covidwho-20609

ABSTRACT

Background: The clinical presentation of SARS-CoV-2-infected pneumonia (COVID-19) resembles that of other etiologies of community-acquired pneumonia (CAP). We aimed to identify clinical laboratory features to distinguish COVID-19 from CAP. Methods: We compared the hematological and biochemical features of 84 patients with COVID-19 at hospital admission and 221 patients with CAP. Parameters independently predictive of COVID-19 were calculated by multivariate logistic regression. The receiver operating characteristic (ROC) curves were generated and the area under the ROC curve (AUC) was measured to evaluate the discriminative ability. Results: Most hematological and biochemical indexes of patients with COVID-19 were significantly different from patients with CAP. Nine laboratory parameters were identified to be predictive of a diagnosis of COVID-19. The AUCs demonstrated good discriminatory ability for red cell distribution width (RDW) with an AUC of 0.87 and hemoglobin with an AUC of 0.81. Red blood cell, albumin, eosinophil, hematocrit, alkaline phosphatase, and mean platelet volume had fair discriminatory ability. Combinations of any two parameters performed better than did the RDW alone. Conclusions: Routine laboratory examinations may be helpful for the diagnosis of COVID-19. Application of laboratory tests may help to optimize the use of isolation rooms for patients when they present with unexplained febrile respiratory illnesses.

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