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1.
EBioMedicine ; 75: 103811, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1638699

ABSTRACT

BACKGROUND: We report on the safety and immunogenicity of V591, a measles vector-based SARS-CoV-2 vaccine candidate. METHODS: In this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial, healthy adults with no history of COVID-19 disease were assigned to intramuscular injection of V591 or placebo (4:1 ratio). In part 1, younger adults (18-55 years) received V591 median tissue culture infectious dose (TCID50)-levels of 1×105 or 1×106 or placebo, 56 days apart. In part 2, younger and older (>55 years) adults received a single dose of one of four (104/105/106/107) or one of two (105/106) V591 TCID50 levels, respectively, or placebo. PRIMARY OUTCOME: safety/tolerability. Secondary outcome: humoral immunogenicity. ClinicalTrials.gov: NCT04498247. FINDINGS: From August-December 2020, 444 participants were screened and 263 randomised (210 V591; 53 placebo); 262 received at least one and 10 received two doses of V591 or placebo. Adverse events were experienced by 140/209 (67.0%) V591 dose-group participants and 37/53 (69.8%) placebo-group participants following injection 1; most frequent were fatigue (57 [27.3%] vs 20 [37.7%]), headache (57 [27.3%] vs 19 [35.8%]), myalgia (35 [16.7%] vs 10 [18.9%]), and injection-site pain (35 [16.7%] vs 4 [7.5%]). No deaths nor vaccine-related serious adverse events occurred. At Day 29, no anti-SARS-CoV-2 spike serum neutralising antibody and IgG-responses were identified in placebo or the three lower V591 dose-groups; responses were detected with V591 1×107 TCID50, although titres were lower than convalescent serum. INTERPRETATION: V591 was generally well tolerated, but immunogenicity was insufficient to warrant continued development. FUNDING: Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

2.
PLoS Negl Trop Dis ; 16(1): e0010048, 2022 01.
Article in English | MEDLINE | ID: covidwho-1606114

ABSTRACT

BACKGROUND: The first community transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant of concern (VOC) in Guangzhou, China occurred between May and June 2021. Herein, we describe the epidemiological characteristics of this outbreak and evaluate the implemented containment measures against this outbreak. METHODOLOGY/PRINCIPAL FINDINGS: Guangzhou Center for Disease Control and Prevention provided the data on SARS-CoV-2 infections reported between 21 May and 24 June 2021. We estimated the incubation period distribution by fitting a gamma distribution to the data, while the serial interval distribution was estimated by fitting a normal distribution. The instantaneous effective reproductive number (Rt) was estimated to reflect the transmissibility of SARS-CoV-2. Clinical severity was compared for cases with different vaccination statuses using an ordinal regression model after controlling for age. Of the reported local cases, 7/153 (4.6%) were asymptomatic. The median incubation period was 6.02 (95% confidence interval [CI]: 5.42-6.71) days and the means of serial intervals decreased from 5.19 (95% CI: 4.29-6.11) to 3.78 (95% CI: 2.74-4.81) days. The incubation period increased with age (P<0.001). A hierarchical prevention and control strategy against COVID-19 was implemented in Guangzhou, with Rt decreasing from 6.83 (95% credible interval [CrI]: 3.98-10.44) for the 7-day time window ending on 27 May 2021 to below 1 for the time window ending on 8 June and thereafter. Individuals with partial or full vaccination schedules with BBIBP-CorV or CoronaVac accounted for 15.3% of the COVID-19 cases. Clinical symptoms were milder in partially or fully vaccinated cases than in unvaccinated cases (odds ratio [OR] = 0.26 [95% CI: 0.07-0.94]). CONCLUSIONS/SIGNIFICANCE: The hierarchical prevention and control strategy against COVID-19 in Guangzhou was timely and effective. Authorised inactivated vaccines are likely to contribute to reducing the probability of developing severe disease. Our findings have important implications for the containment of COVID-19.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/epidemiology , COVID-19/prevention & control , Communicable Disease Control/methods , SARS-CoV-2/isolation & purification , Adult , Aged , Basic Reproduction Number , COVID-19/transmission , China/epidemiology , Female , Humans , Male , Middle Aged , Primary Prevention/methods , Severity of Illness Index , Vaccination/statistics & numerical data , Young Adult
4.
World J Clin Cases ; 9(29): 8647-8657, 2021 Oct 16.
Article in English | MEDLINE | ID: covidwho-1502801

ABSTRACT

Personalized medicine is the tailor-made clinical treatment to the individual characteristics of each patient. It may be considered an extension of traditional approaches to knowing and treating diseases. Personalized medicine has the potential to change the way of identification and management of health problems. Coronavirus disease 2019 (COVID-19) is an infectious disease that primarily affects the patients' lungs. The first case of pneumonia of unknown cause was reported in Wuhan, China on December 31, 2019. As thus, we are quickly approaching the era of personalized medicine. This review discusses the practices currently used in the management of COVID-19 and how they relate to personalized medicine.

5.
J Affect Disord ; 297: 314-320, 2022 01 15.
Article in English | MEDLINE | ID: covidwho-1482663

ABSTRACT

BACKGROUND: The COVID-19 pandemic has brought a lot of working stress to medical workers and has a certain impact on their mental health. Working stress is closely related to the increase in anxiety, but few studies have explored whether their relationship will be affected by positive psychological factors in the special situation. METHODS: 798 medical workers were investigated online after the outbreak of the COVID-19 (10 February to 1 March 2020) in China. The relevant questionnaires were used to evaluate working stress, anxiety, sense of control, and psychological capital. The moderated mediation model test was performed using the SPSS software and PROCESS macro program. RESULTS: Working stress could directly affect anxiety, and indirectly affect anxiety through sense of control. In addition, psychological capital moderated the direct effect of working stress on anxiety, which is more effective at high level of psychological capital. Psychological capital also moderated the second half of the indirect effect of working stress on anxiety, at low level of psychological capital, sense of control was more effective in predicting anxiety. LIMITATIONS: All the data in this study was collected through online questionnaire. The anxiety response measured in this study cannot be specific to the viral epidemic. CONCLUSIONS: Under the COVID-19 epidemic situation, for medical workers, low sense of control and low level of psychological capital may be important risk factors of anxiety caused by working stress. Thus, strengthening the sense of control and psychological capital of medical workers would be helpful to reduce their anxiety and maintain their mental health.


Subject(s)
COVID-19 , Anxiety/epidemiology , China/epidemiology , Depression , Humans , Pandemics , SARS-CoV-2 , Surveys and Questionnaires
6.
BMJ Open ; 11(10): e043790, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1448013

ABSTRACT

OBJECTIVES: As early prediction of severe illness and death for patients with coronavirus disease 2019 (COVID-19) is important, we aim to explore the clinical value of laboratory indicators in evaluating the progression and prognosis of patients with COVID-19. DESIGN: Retrospective cohort study. SETTING: Hospital-based study in China. PARTICIPANTS: Adult patients with COVID-19 from December 15, 2019 to March 15, 2020. END POINT: Disease severity and mortality. METHODS: Clinical data of 638 patients with COVID-19 were collected and compared between severe and non-severe groups. The predictive ability of laboratory indicators in disease progression and prognosis of COVID-19 was analysed using the receiver operating characteristic curve. The survival differences of COVID-19 patients with different levels of laboratory indicators were analysed utilising Kaplan-Meier analysis. RESULTS: 29.8% (190/638) of patients with COVID-19 progressed to severe. Compared with patients with no adverse events, C reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and D-dimer were significantly higher in severe patients with adverse events, such as acute myocardial injury, respiratory failure, acute kidney injury, mechanical ventilation, intensive care unit admission, multiple organ dysfunction syndromes and death (all p<0.05). The multivariate logistic analysis suggested that CRP, NLR and D-dimer were independent risk factors for the disease progression of COVID-19 (all p<0.05). The model combining all of them owned the highest area under the receiver operating characteristic curve (AUC) predicting disease progression and death of COVID-19, with AUC of 0.894 (95% CI 0.857 to 0.931) and 0.918 (95% CI 0.873 to 0.962), respectively. Survival analysis suggested that the patients with a high level of CRP, NLR or D-dimer performed shorter overall survival time (all p<0.05). CONCLUSIONS: The combination of CRP, NLR and D-dimer could be an effective predictor for the aggravation and death in patients with COVID-19. The abnormal expression of these indicators might suggest a strong inflammatory response and multiple adverse events in patients with severe COVID-19.


Subject(s)
COVID-19 , Laboratories , Adult , Disease Progression , Humans , Neutrophils , Prognosis , ROC Curve , Retrospective Studies , SARS-CoV-2
7.
iScience ; 24(10): 103186, 2021 Oct 22.
Article in English | MEDLINE | ID: covidwho-1446742

ABSTRACT

The COVID-19 pandemic has caused over 220 million infections and 4.5 million deaths worldwide. Current risk factor cannot fully explain the diversity in disease severity. Here, we present a comprehensive analysis of a broad range of patients' laboratory and clinical assessments to investigate the genetic contributions to COVID-19 severity. By performing GWAS analysis, we discovered several concrete associations for laboratory traits and used Mendelian randomization (MR) analysis to further investigate the causality of traits on disease severity. Two causal traits, WBC counts and cholesterol levels, were identified based on MR study, and their functional genes are located at genes MHC complex and ApoE, respectively. Our gene-based analysis and GSEA revealed four interferon pathways, including type I interferon receptor binding and SARS coronavirus and innate immunity. We hope that our work will contribute to studying the genetic mechanisms of disease and serve as a useful reference for COVID-19 diagnosis and treatment.

8.
Energy (Oxf) ; 239: 122166, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1446606

ABSTRACT

The COVID-19 pandemic affects all the aspects of modern society worldwide, especially in the power sector. Measures of flexibility enhancement are regarded as solutions to guarantee reliable and flexible electricity supply in such an emergency. This study aims at investigating the impact of flexibility enhancement measures (electricity storage and flexible demand) in different situations of the preliminary COVID-19 pandemic. Case studies in different regions (Denmark, the Netherlands, and the Sichuan province of China) are conducted and assessed using the hourly simulation tool EnergyPLAN. These regions own different electricity supply mix and level of renewable electricity. It is found that the flexible demand measure within one day or one week can hardly eliminate the electricity imbalance caused by either the pandemic or the increasing renewable electricity. The monthly flexible demand is effective for balancing, but its potential in these regions is not enough. However, electricity storage measure enhances the electricity balance even during the most extreme situation of the pandemic. From the economic perspective, electricity storage measure leads to an increase of up to 15% in total system costs, while flexible demand measure has a negligible effect on costs. This study serves as the first step to understand the performance of flexibility enhancement measures in the power sector under the shock of a pandemic.

9.
Psychoanalysis, Culture & Society ; : 1-15, 2021.
Article in English | Academic Search Complete | ID: covidwho-1442859

ABSTRACT

The COVID-19 pandemic has produced a collective paranoia which is not only driven by our psychic anxiety but also mirrors the irrationality of the crisis and the failure of global governance. During such catastrophic times, in which the state has failed to create a sustainable civil society, scholars such as Melanie Klein, Silvan Tomkins, and Eve Sedgwick have theorized the ways in which we may turn paranoia away from its destructive tendency toward a reparative practice of relationship-building and collective action. I discuss the limits of a clinical approach to paranoia and propose a reparative practice of the global psyche toward social transformation, especially in relation to the rise of anti-Asian violence during the pandemic. [ABSTRACT FROM AUTHOR] Copyright of Psychoanalysis, Culture & Society is the property of Palgrave Macmillan Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

10.
Sci Total Environ ; 805: 150355, 2022 Jan 20.
Article in English | MEDLINE | ID: covidwho-1415772

ABSTRACT

Post COVID-19, mucormycosis occurred after the SARS-CoV-2 has rampaged the human population and is a scorching problem among the pandemic globally, particularly among Asian countries. Invasive mucormycosis has been extensively reported from mild to severe COVID-19 survivors. The robust predisposing factor seems to be uncontrolled diabetes mellitus, comorbidity and immunosuppression acquired through steroid therapy. The prime susceptive reason for the increase of mucormycosis cases is elevated iron levels in the serum of the COVID survivors. A panoramic understanding of the infection has been elucidated based on clinical manifestation, genetic and non- genetic mechanisms of steroid drug administration, biochemical pathways and immune modulated receptor associations. This review lime-lights and addresses the "What", "Why", "How" and "When" about the COVID-19 associated mucormycosis (CAM) in a comprehensive manner with a pure intention to bring about awareness to the common public as the cases are inevitably and exponentially increasing in India and global countries as well. The article also unearthed the pathogenesis of mucormycosis and its association with the COVID-19 sequela, the plausible routes of entry, diagnosis and counter remedies to keep the infection at bay. Cohorts of case reports were analysed to spotlight the link between the pandemic COVID-19 and the nightmare-mucormycosis.


Subject(s)
COVID-19 , Mucormycosis , Comorbidity , Fungi , Humans , Mucormycosis/epidemiology , Pandemics , SARS-CoV-2
11.
Front Public Health ; 9: 670889, 2021.
Article in English | MEDLINE | ID: covidwho-1399185

ABSTRACT

COVID-19, the coronavirus disease 2019; SARS-CoV-2, the coronavirus 2; ACE2, angiotensin converting enzyme 2; S protein, spiked glycoprotein; TMPRSS2, transmembrane serine protease 2; WHO, World Health Organization. Purpose: Although the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2, has been viably controlled in China, a new normal in healthcare strategies has become standard in China and worldwide. We conducted a questionnaire study to disseminate the experience from China in terms of urology outpatient prevention and control measures under standardized prevention policies against COVID-19. Participants and Methods: From May 3, 2020 to June 25, 2020, we conducted an anonymous cross-sectional questionnaire study, focused on the status of and experiences with outpatient urology prevention and control measures during the COVID-19 pandemic. The targeted respondents were urologists in mainland China, covering all levels of hospitals and clinics. Results: A total of 216 (97%) valid responses were collected. We found that 183 (85%) respondents were from outside of Hubei province in China. One-hundred-and-fifty-eight (73%) respondents believed that SARS-CoV-2 could be detected in urine, and that protection against urine exposure was needed. Over 80% of respondents recommended WeChat application or similar online video meetings for virtual outpatient consultations. The suggested flowcharts and recommendations to prevent new cases were easy to understand and approved by most physicians, which could provide reference for outpatient prevention and control. We still need to make adequate preparations under the new normal of the COVID-19 Epidemic, especially for those suspected of being infected. Conclusions: Although the scientific validation of the questionnaire is limited, it provides a first snapshot of the experiences relating to the prevention and control measures in urology clinics in China, and can inform future policies in this field.


Subject(s)
COVID-19 , Urology , China/epidemiology , Cross-Sectional Studies , Humans , Pandemics , SARS-CoV-2 , Surveys and Questionnaires
12.
Emerg Microbes Infect ; 10(1): 1751-1759, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1393119

ABSTRACT

The effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant, which has been associated with greater transmissibility and virulence, remains unclear. We conducted a test-negative case-control study to explore the vaccine effectiveness (VE) in real-world settings. We recruited participants aged 18-59 years who consisted of SARS-CoV-2 test-positive cases (n = 74) and test-negative controls (n = 292) during the outbreak of the Delta variant in May 2021 in Guangzhou city, China. Vaccination status was compared to estimate The VE of SARS-CoV-2 inactivated vaccines. A single dose of inactivated SARS-CoV-2 vaccine yielded the VE of only 13.8%. After adjusting for age and sex, the overall VE for two-dose vaccination was 59.0% (95% confidence interval: 16.0% to 81.6%) against coronavirus disease 2019 (COVID-19) and 70.2% (95% confidence interval: 29.6-89.3%) against moderate COVID-19 and 100% against severe COVID-19 which might be overestimated due to the small sample size. The VE of two-dose vaccination against COVID-19 reached 72.5% among participants aged 40-59 years, and was higher in females than in males against COVID-19 and moderate diseases. While single dose vaccination was not sufficiently protective, the two-dose dosing scheme of the inactivated vaccines was effective against the Delta variant infection in real-world settings, with the estimated efficacy exceeding the World Health Organization minimal threshold of 50%.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , SARS-CoV-2/genetics , Adolescent , Adult , Age Distribution , COVID-19/classification , COVID-19 Vaccines/administration & dosage , Case-Control Studies , China , Disease Outbreaks , Female , Genetic Variation , Humans , Male , Middle Aged , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/standards , Young Adult
13.
PLoS Pathog ; 17(8): e1009758, 2021 08.
Article in English | MEDLINE | ID: covidwho-1352713

ABSTRACT

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development.


Subject(s)
COVID-19 , Communicable Diseases, Emerging , Disease Models, Animal , 3T3 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , COVID-19/immunology , COVID-19/pathology , COVID-19/physiopathology , Chlorocebus aethiops , Dependovirus/genetics , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Transduction, Genetic , Vero Cells
14.
Front Med (Lausanne) ; 8: 694367, 2021.
Article in English | MEDLINE | ID: covidwho-1323081

ABSTRACT

The 2019 coronavirus disease (COVID-19) is a highly contagious and deadly disease. The elderly people are often accompanied by chronic inflammation and immunodeficiency, showing a frail state. The strength, endurance, and physiological function of the elderly are significantly decreased, and the ability to deal with stress response is weakened. They are the high-risk group that suffering from COVID-19, and rapidly developing to critical illness. Several recent studies suggest that the incidence rate of COVID-19 in elderly patients with frailty is high. Early assessment, detection, and effective intervention of frailty in COVID-19 patients are conducive to significantly improve the quality of life and improve prognosis. However, there are insufficient understanding and standards for the current evaluation methods, pathogenesis and intervention measures for COVID-19 combined with frailty. This study reviews the progress of the research on the potential pathogenesis, evaluation methods and intervention measures of the elderly COVID-19 patients with frailty, which provides a reference for scientific and reasonable comprehensive diagnosis and treatment in clinical.

15.
Cell Rep Med ; 2(8): 100369, 2021 Aug 17.
Article in English | MEDLINE | ID: covidwho-1322391

ABSTRACT

There is an urgent need to identify which COVID-19 patients will develop life-threatening illness so that medical resources can be optimally allocated and rapid treatment can be administered early in the disease course, when clinical management is most effective. To aid in the prognostic classification of disease severity, we perform untargeted metabolomics on plasma from 339 patients, with samples collected at six longitudinal time points. Using the temporal metabolic profiles and machine learning, we build a predictive model of disease severity. We discover that a panel of metabolites measured at the time of study entry successfully determines disease severity. Through analysis of longitudinal samples, we confirm that most of these markers are directly related to disease progression and that their levels return to baseline upon disease recovery. Finally, we validate that these metabolites are also altered in a hamster model of COVID-19.

16.
Front Endocrinol (Lausanne) ; 12: 611526, 2021.
Article in English | MEDLINE | ID: covidwho-1305635

ABSTRACT

Background: It has been reported that dyslipidemia is related to coronavirus-related diseases. Critical patients with coronavirus disease 2019 (COVID-19) who suffered from multiple organ dysfunctions were treated in the intensive care unit (ICU) in Wuhan, China. Whether the lipids profile was associated with the prognosis of COVID-19 in critical patients remained unclear. Methods: A retrospective study was performed in critical patients (N=48) with coronavirus disease 2019 in Leishenshan hospital between February and April 2020 in Wuhan. The parameters including lipid profiles, liver function, and renal function were collected on admission day, 2-3days after the admission, and the day before the achievement of clinical outcome. Results: Albumin value and creatine kinase (ck) value were statistically decreased at 2-3 days after admission compared with those on admission day (P<0.05). Low density lipoprotein (LDL-c), high density lipoprotein (HDL-c), apolipoprotein A (ApoA), and apolipoprotein A (Apo B) levels were statistically decreased after admission (P<0.05). Logistic regression showed that HDL-c level both on admission day and the day before the achievement of clinical outcome were negatively associated with mortality in critical patients with COVID-19. Total cholesterol (TC) level at 2-3days after admission was related to mortality in critical patients with COVID-19. Conclusions: There were lipid metabolic disorders in the critical patients with COVID-19. Lower levels of HDL-c and TC were related to the progression of critical COVID-19.


Subject(s)
COVID-19/mortality , Dyslipidemias/epidemiology , Hospital Mortality , Multiple Organ Failure/mortality , Aged , Aged, 80 and over , Apolipoproteins A/blood , Apolipoproteins B/blood , COVID-19/blood , COVID-19/epidemiology , China/epidemiology , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Critical Illness , Dyslipidemias/blood , Female , Humans , Male , Middle Aged , Multiple Organ Failure/blood , Multiple Organ Failure/epidemiology , Retrospective Studies , Risk Factors , SARS-CoV-2 , Severity of Illness Index
17.
Int J Med Sci ; 18(12): 2545-2550, 2021.
Article in English | MEDLINE | ID: covidwho-1248381

ABSTRACT

Objectives: The epidemiological and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) have been researched. However, the prevalence of repositivity by real-time PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. Methods: A retrospective study was conducted involving 599 discharged patients with COVID-19 in a single medical centre. The clinical features of patients during their hospitalization and 14-day post-discharge quarantine were collected. Results: A total of 122 patients (20.4%) out of 599 patients retested positive after discharge. Specifically, 94 (15.7%) retested positive within 24 h of discharge, and another 28 patients (4.7%) were repositive on day 7 after discharge, although none showed any clinical symptomatic recurrence. Both repositives and non­repositives have similar patterns of IgG and IgM. Notably, the length of hospitalization of non-repositive patients was longer than that of 24-h repositive patients and 7-day repositive patients. In addition, the length of hospitalization of 24-h repositive patients was shorter than that of 7-day repositive patients, indicating that the length of hospitalization was also a determinant of viral shedding. Conclusion: Our study provides further information for improving the management of recovered and discharged patients, and further studies should be performed to elucidate the infectiveness of individuals with prolonged or RNA repositivity.


Subject(s)
Aftercare/statistics & numerical data , COVID-19 Nucleic Acid Testing/statistics & numerical data , COVID-19/diagnosis , SARS-CoV-2/isolation & purification , Adolescent , Adult , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/epidemiology , COVID-19/therapy , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Length of Stay/statistics & numerical data , Male , Middle Aged , Patient Discharge , RNA, Viral/isolation & purification , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction/statistics & numerical data , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Severity of Illness Index , Virus Shedding/immunology , Young Adult
18.
Int J Mol Sci ; 22(10)2021 May 16.
Article in English | MEDLINE | ID: covidwho-1234743

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and ß-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin-angiotensin-aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill's causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.


Subject(s)
Adaptive Immunity , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Vitamin D/metabolism , Vitamin D/pharmacology , COVID-19/mortality , COVID-19/physiopathology , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokines/metabolism , Humans , Receptors, Virus/metabolism , Renin-Angiotensin System/physiology
19.
Hum Pathol ; 114: 110-119, 2021 08.
Article in English | MEDLINE | ID: covidwho-1213257

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although viral infection is known to trigger inflammatory processes contributing to tissue injury and organ failure, it is unclear whether direct viral damage is needed to sustain cellular injury. An understanding of pathogenic mechanisms has been handicapped by the absence of optimized methods to visualize the presence and distribution of SARS-CoV-2 in damaged tissues. We first developed a positive control cell line (Vero E6) to validate SARS-CoV-2 detection assays. We then evaluated multiple organs (lungs, kidneys, heart, liver, brain, intestines, lymph nodes, and spleen) from fourteen COVID-19 autopsy cases using immunohistochemistry (IHC) for the spike and the nucleoprotein proteins, and RNA in situ hybridization (RNA ISH) for the spike protein mRNA. Tissue detection assays were compared with quantitative polymerase chain reaction (qPCR)-based detection. SARS-CoV-2 was histologically detected in the Vero E6 positive cell line control, 1 of 14 (7%) lungs, and none (0%) of the other 59 organs. There was perfect concordance between the IHC and RNA ISH results. qPCR confirmed high viral load in the SARS-CoV-2 ISH-positive lung tissue, and absent or low viral load in all ISH-negative tissues. In patients who die of COVID-19-related organ failure, SARS-CoV-2 is largely not detectable using tissue-based assays. Even in lungs showing widespread injury, SARS-CoV-2 viral RNA or proteins were detected in only a small minority of cases. This observation supports the concept that viral infection is primarily a trigger for multiple-organ pathogenic proinflammatory responses. Direct viral tissue damage is a transient phenomenon that is generally not sustained throughout disease progression.


Subject(s)
COVID-19/pathology , Liver/virology , Lung/virology , SARS-CoV-2/pathogenicity , Animals , Autopsy/methods , COVID-19/virology , Chlorocebus aethiops , Disease Progression , Humans , Immunohistochemistry/methods , Liver/chemistry , Liver/pathology , Lung/pathology , RNA, Viral/metabolism , Vero Cells/virology , Viral Load/methods
20.
Nat Biomed Eng ; 5(8): 815-829, 2021 08.
Article in English | MEDLINE | ID: covidwho-1213929

ABSTRACT

The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 Testing/methods , COVID-19/drug therapy , Lab-On-A-Chip Devices , Animals , COVID-19/diagnosis , COVID-19/virology , Cell Line , Cricetinae , Female , Green Fluorescent Proteins , Humans , Male , SARS-CoV-2/drug effects , Virus Internalization/drug effects
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