Research progress on SARS, MERS and COVID-19 coronavirus

beta-Coronavirus(beta-CoV) contains a type of related viruses that can cause human respiratory infections.It is widespread in nature and can cause serious harm to humans or animals. The infection of the virus has the characteristics of high infectivity, wide epidemic, strong suddenness, and without effective preventive medication, which imposes a large medical burden on the country and patients. This review briefly summarizes the epidemic situation, transmission route, pathogenicity, pathogenesis and latest progress in drugs and vaccines of acute respiratory syndrome coronavirus(SARS-CoV), Middle East respiratory syndrome coronavirus(MERS-CoV) and the severe acute respiratory syndrome coronavirus 2(SARS-COV-2) since December 2019.

Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants.

It is urgent to develop more effective mRNA vaccines against the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants owing to the immune escape. Here, we constructed a novel mRNA delivery system [IC8/Mn lipid nanoparticles (IC8/Mn LNPs)]with high immunogenicity, via introducing a stimulator of interferon genes (STING) agonist [manganese (Mn)] based on a newly synthesized ionizable lipid (IC8). It was found that Mn can not only promote maturation of antigen-presenting cells via activating STING pathway but also improve mRNA expression by facilitating lysosomal escape for the first time. Subsequently, IC8/Mn LNPs loaded with mRNA encoding the Spike protein of SARS-CoV-2 Delta or Omicron variant (IC8/Mn@D or IC8/Mn@O) were prepared. Both mRNA vaccines induced substantial specific immunoglobulin G responses against Delta or Omicron. IC8/Mn@D displayed strong pseudovirus neutralization ability, T helper 1-biased immune responses, and good safety. It can be concluded that IC8/Mn LNPs have great potential for developing Mn-coordinated mRNA vaccines with robust immunogenicity and good safety.

Tractable Bayes of skew-elliptical link models for correlated binary data.

Correlated binary response data with covariates are ubiquitous in longitudinal or spatial studies. Among the existing statistical models, the most well-known one for this type of data is the multivariate probit model, which uses a Gaussian link to model dependence at the latent level. However, a symmetric link may not be appropriate if the data are highly imbalanced. Here, we propose a multivariate skew-elliptical link model for correlated binary responses, which includes the multivariate probit model as a special case. Furthermore, we perform Bayesian inference for this new model and prove that the regression coefficients have a closed-form unified skew-elliptical posterior with an elliptical prior. The new methodology is illustrated by an application to COVID-19 data from three different counties of the state of California, USA. By jointly modeling extreme spikes in weekly new cases, our results show that the spatial dependence cannot be neglected. Furthermore, the results also show that the skewed latent structure of our proposed model improves the flexibility of the multivariate probit model and provides a better fit to our highly imbalanced dataset.

Clinical characteristics and risk factors associated with mortality in patients with severe community-acquired pneumonia and type 2 diabetes mellitus.

BACKGROUND: The present study was performed to investigate the impacts of type 2 diabetes mellitus (T2DM) on severe community-acquired pneumonia (SCAP) and to develop a novel prediction model for mortality in SCAP patients with T2DM. METHODS: This was a retrospective observational study conducted in consecutive adult patients with SCAP admitted to the intensive care unit (ICU) of West China Hospital, Sichuan University, China, between September 2011 and September 2019. The primary outcome was hospital mortality. A propensity score matching (PSM) analysis model with a 1:2 ratio was used for the comparisons of clinical characteristics and outcomes between T2DM and nondiabetic patients. The independent risk factors were identified via univariate and then multivariable logistic regression analysis and were then used to establish a nomogram. RESULTS: In total, 1262 SCAP patients with T2DM and 2524 matched patients without T2DM were included after PSM. Patients with T2DM had longer ICU length of stay (LOS) (13 vs. 12 days, P = 0.016) and higher 14-day mortality (15% vs. 10.8%, P < 0.001), 30-day mortality (25.7% vs. 22.7%, P = 0.046), ICU mortality (30.8% vs. 26.5%, P = 0.005), and hospital mortality (35.2% vs. 31.0%, P = 0.009) than those without T2DM. In SCAP patients with T2DM, the independent risk factors for hospital mortality were increased numbers of comorbidities and diabetes-related complications; elevated C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), brain natriuretic peptide (BNP) and blood lactate; as well as decreased blood pressure on admission. The nomogram had a C index of 0.907 (95% CI: 0.888, 0.927) in the training set and 0.873 (95% CI: 0.836, 0.911) in the testing set, which was superior to the pneumonia severity index (PSI, AUC: 0.809, 95% CI: 0.785, 0.833). The calibration curve and decision curve analysis (DCA) also demonstrated its accuracy and applicability. CONCLUSIONS: SCAP patients with T2DM had worse clinical outcomes than nondiabetic patients. The nomogram has good predictive performance for hospital mortality and might be generally applied after more external validations.

Sedation, Analgesia, and Muscle Relaxation During VV-ECMO Therapy in Patients With Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2): A Single-Center, Retrospective, Observational Study.

Objective: The pharmacokinetics and pharmacodynamics of ECMO-supported sedative, analgesic, and muscle relaxants have changed, but there are insufficient data to determine the optimal dosing strategies for these agents. Sedation, analgesia and muscle relaxation therapy for patients with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) receiving ECMO support are more specific and have not been fully reported. This study observed and evaluated the use of sedative and analgesic drugs and muscle relaxants in SARS-CoV-2 patients treated with VV-ECMO. Methods: This study was a single-center, retrospective and observational study. Our study includes 8 SARS-CoV-2 patients treated with VV-ECMO in an intensive care unit at Shanghai Public Health Center from February to June 2020. We collected the demographic data from these patients and the dose and course of sedation, analgesia, and muscle relaxants administered during ECMO treatment. Results: The doses of sedative, analgesic and muscle relaxant drugs used in patients with VV-ECMO were significant. Over time, the doses of drugs that were used were increased, and the course of muscle relaxant treatment was extended. Conclusion: Sedation, analgesia, and muscle relaxant use require individualized titration in patients with SARS-CoV-2 who have respiratory failure and who are receiving VV-ECMO.

Research progress of SARS-COV and MERS-COV and SARS-COV-2

β-coronavirus (β-coronavirus, β-COV) is a kind of related viruses that can cause human respiratory infections. It exists widely in nature and can cause serious harm to humans or animals. The virus infection has the characteristics of high contagiousness, wide epidemic, strong suddenness and no effective preventive medicine, which has caused a large medical burden on countries and citizens in the world. This article mainly focuses on severe acute respiratory syndrome coronavirus (SARS-COV) and Middle East respiratory syndrome coronavirus (MERS-COV), as well as new coronaviruses since December 2019 (Severe Acute Respiratory Syndrome Coronavirus 2, SARS-COV-2) The epidemiological profile, transmission route, pathogenicity and pathogenic mechanism, drugs and vaccines and other latest developments are reviewed, aiming to better prevent and control highly pathogenic The human coronavirus provides the basis.

Severe Adaptive Immune Suppression May Be Why Patients With Severe COVID-19 Cannot Be Discharged From the ICU Even After Negative Viral Tests.

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the "dysregulated host response" to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.

The impact of lockdown on nitrogen dioxide (NO2) over Central Asian countries during the COVID-19 pandemic.

Nitrogen dioxide (NO2) is one of the main air pollutants, formed due to both natural and anthropogenic processes, which has a significant negative impact on human health. The COVID-19 pandemic has prompted countries to take various measures, including social distancing or stay-at-home orders. This study analyzes the impact of COVID-19 lockdown measures on nitrogen dioxide (NO2) changes in Central Asian countries. Data from TROPOspheric Monitoring Instrument (TROPOMI) on the Sentinel-5 Precursor satellite, as well as meteorological data, make it possible to assess changes in NO2 concentration in countries and major cities in the region. In particular, the obtained satellite data show a decreased tropospheric column of NO2. Its decrease during the lockdown (March 19-April 14) ranged from - 5.1% (Tajikistan) to - 11.6% (Turkmenistan). Based on the obtained results, it can be concluded that limitations in anthropogenic activities have led to improvements in air quality. The possible influence of meteorology is not assessed in this study, and the implied uncertainties cannot be quantified. In this way, the level of air pollution is expected to decrease as long as partial or complete lockdown continues.

Association between glucocorticoids treatment and viral clearance delay in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Evidence of glucocorticoids on viral clearance delay of COVID-19 patients is not clear. METHODS: In this systematic review and meta-analysis, we searched for studies on Medline, Embase, EBSCO, ScienceDirect, Web of Science, Cochrane Library, and ClinicalTrials.gov from 2019 to April 20, 2021. We mainly pooled the risk ratios (RRs) and mean difference (MD) for viral clearance delay and did subgroup analyses by the severity of illness and doses of glucocorticoids. RESULTS: 38 studies with a total of 9572 patients were identified. Glucocorticoids treatment was associated with delayed viral clearance in COVID-19 patients (adjusted RR 1.52, 95% CI 1.29 to 1.80, I2 = 52%), based on moderate-quality evidence. In subgroup analyses, risk of viral clearance delay was significant both for COVID-19 patients being mild or moderate ill (adjusted RR 1.86, 95% CI 1.35 to 2.57, I2 = 48%), and for patients of being severe or critical ill (adjusted RR 1.59, 95% CI 1.23 to 2.07, I2 = 0%); however, this risk significantly increased for patients taking high doses (unadjusted RR 1.85, 95% CI 1.08 to 3.18; MD 7.19, 95% CI 2.78 to 11.61) or medium doses (adjusted RR 1.86, 95% CI 0.96 to 3.62, I2 = 45%; MD 3.98, 95% CI 3.07 to 4.88, I2 = 4%), rather those taking low doses (adjusted RR 1.38, 95% CI 0.94 to 2.02, I2 = 59%; MD 1.46, 95% CI -0.79 to 3.70, I2 = 82%). CONCLUSIONS: Glucocorticoids treatment delayed viral clearance in COVID-19 patients of taking high doses or medium doses, rather in those of taking low doses of glucocorticoids.

Quantification of Cytokine Storms During Virus Infections.

Highly pathogenic virus infections usually trigger cytokine storms, which may have adverse effects on vital organs and result in high mortalities. The two cytokines interleukin (IL)-4 and interferon (IFN)-γ play key roles in the generation and regulation of cytokine storms. However, it is still unclear whether the cytokine with the largest induction amplitude is the same under different virus infections. It is unknown which is the most critical and whether there are any mathematical formulas that can fit the changing rules of cytokines. Three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), three influenza viruses (2009H1N1, H5N1 and H7N9), Ebola virus, human immunodeficiency virus, dengue virus, Zika virus, West Nile virus, hepatitis B virus, hepatitis C virus, and enterovirus 71 were included in this analysis. We retrieved the cytokine fold change (FC), viral load, and clearance rate data from these highly pathogenic virus infections in humans and analyzed the correlations among them. Our analysis showed that interferon-inducible protein (IP)-10, IL-6, IL-8 and IL-17 are the most common cytokines with the largest induction amplitudes. Equations were obtained: the maximum induced cytokine (max) FC = IFN-γ FC × (IFN-γ FC/IL-4 FC) (if IFN-γ FC/IL-4 FC > 1); max FC = IL-4 FC (if IFN-γ FC/IL-4 FC < 1). For IFN-γ-inducible infections, 1.30 × log2 (IFN-γ FC) = log10 (viral load) - 2.48 - 2.83 × (clearance rate). The clinical relevance of cytokines and their antagonists is also discussed.

Anti-SARS-CoV-2 IgG levels in relation to disease severity of COVID-19.

The durability of infection-induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity has crucial implications for reinfection and vaccine effectiveness. However, the relationship between coronavirus disease 2019 (COVID-19) severity and long-term anti-SARS-CoV-2 immunoglobulin G (IgG) antibody level is poorly understood. Here, we measured the longevity of SARS-CoV-2-specific IgG antibodies in survivors who had recovered from COVID-19 1 year previously. In a cohort of 473 survivors with varying disease severity (asymptomatic, mild, moderate, or severe), we observed a positive correlation between virus-specific IgG antibody titers and COVID-19 severity. In particular, the highest virus-specific IgG antibody titers were observed in patients with severe COVID-19. By contrast, 74.4% of recovered asymptomatic carriers had negative anti-SARS-CoV-2 IgG test results, while many others had very low virus-specific IgG antibody titers. Our results demonstrate that SARS-CoV-2-specific IgG persistence and titer depend on COVID-19 severity.

The Role of Alveolar Edema in COVID-19.

The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threatening hypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation-perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar edema in the disease progression has not been discussed comprehensively. Since the exudation of pulmonary edema fluid was extremely serious in COVID-19 patients, we bring out a hypothesis that severity of alveolar edema may determine the size of poorly-ventilated area and the blood oxygen content. Treatments to pulmonary edema (conservative fluid management, exogenous surfactant replacements and ethanol-oxygen vapor therapy hypothetically) may be greatly helpful for reducing the occurrences of severe cases. Given that late mechanical ventilation may cause mucus (edema fluid) to be blown deep into the small airways, oxygen therapy should be given at the early stages. The optimal time and blood oxygen saturation (SpO2) threshold for oxygen therapy are also discussed.

Comparison of Associations Between Glucocorticoids Treatment and Mortality in COVID-19 Patients and SARS Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The response to glucocorticoids treatment may be different between coronavirus disease 2019 (Covid-19) and severe acute respiratory syndrome (SARS). METHODS: In this systematic review and meta-analysis, we searched studies on Medline, Embase, EBSCO, ScienceDirect, Web of Science, Cochrane Library, ClinicalTrials.gov, International Clinical Trials Registry Platform from 2002 to October 7, 2020. We used fixed-effects and random-effects models to compute the risk ratio of death in the group receiving glucocorticoids treatment and the control group for COVID-19 and SARS, respectively. RESULTS: Ten trials and 71 observational studies, with a total of 45,935 patients, were identified. Glucocorticoids treatment was associated with decreased all-cause mortality both in COVID-19 (risk ratio, 0.88; 95% confidence interval, 0.82-0.94; I2 = 26%) and SARS (0.48; 0.29-0.79; 10%), based on high-quality evidence, as well as decreased all-cause mortality-including composite outcome of COVID-19 (0.89; 0.82-0.98; 0%). In subgroup analyses, all-cause mortality was significantly lower among COVID-19 patients being accompanied by severe ARDS but not mild ARDS, taking low-dose or pulse glucocorticoids, being critically severe but not only severe, being of critical severity and old but not young, being of critical severity and men but not women, non-early taking glucocorticoids, taking dexamethasone or methylprednisolone, and with the increased inflammatory state; but for SARS, lower mortality was observed among those who were taking medium-high dose glucocorticoids, being severe or critically severe, early taking glucocorticoids, and taking methylprednisolone or prednisolone. CONCLUSIONS: Glucocorticoids treatment reduced mortality in COVID-19 and SARS patients of critical severity; however, different curative effects existed between the two diseases among subpopulations, mainly regarding sex- and age-specific effects, optimal doses, and use timing of glucocorticoids.

Anticoagulation Management in Severe Coronavirus Disease 2019 Patients on Extracorporeal Membrane Oxygenation.

OBJECTIVE: To explore special coagulation characteristics and anticoagulation management in extracorporeal membrane oxygenation (ECMO)-assisted patients with coronavirus disease 2019 (COVID-19). DESIGN: Single-center, retrospective observation of a series of patients. PARTICIPANTS: Laboratory-confirmed severe COVID-19 patients who received venovenous ECMO support from January 20-May 20, 2020. INTERVENTIONS: This study analyzed the anticoagulation management and monitoring strategies, bleeding complications, and thrombotic events during ECMO support. MEASUREMENTS AND MAIN RESULTS: Eight of 667 confirmed COVID-19 patients received venovenous ECMO and had an elevated D-dimer level before and during ECMO support. An ECMO circuit pack (oxygenator and tubing) was replaced a total of 13 times in all 8 patients, and coagulation-related complications included oxygenator thrombosis (7/8), tracheal hemorrhage (5/8), oronasal hemorrhage (3/8), thoracic hemorrhage (3/8), bleeding at puncture sites (4/8), and cannulation site hemorrhage (2/8). CONCLUSIONS: Hypercoagulability and secondary hyperfibrinolysis during ECMO support in COVID-19 patients are common and possibly increase the propensity for thrombotic events and failure of the oxygenator. Currently, there is not enough evidence to support a more aggressive anticoagulation strategy.

Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019 in Shanghai, China.

Severe cases of coronavirus disease 2019 (COVID-19) cannot be adequately managed with mechanical ventilation alone. The role and outcome of extracorporeal membrane oxygenation (ECMO) in the management of COVID-19 is currently unclear. Eight COVID-19 patients have received ECMO support in Shanghai with seven with venovenous (VV) ECMO support and one veno arterial (VA) ECMO during cardiopulmonary resuscitation. As of March 25, 2020, four patients died (50% mortality), three patients (37.5%) were successfully weaned off ECMO after 22, 40, and 47 days support, respectively, but remain on mechanical ventilation. One patient is still on VV ECMO with mechanical ventilation. The partial pressure of oxygen/fractional of inspired oxygen ratio before ECMO initiation was between 54 and 76, and all were well below 100. The duration of mechanical ventilation before ECMO ranged from 4 to 21 days. Except the one emergent VA ECMO during cardiopulmonary resuscitation, other patients were on ECMO support for between 18 and 47 days. In conclusion, ensuring effective, timely, and safe ECMO support in COVID-19 is key to improving clinical outcomes. Extracorporeal membrane oxygenation support might be an integral part of the critical care provided for COVID-19 patients in centers with advanced ECMO expertise.