ABSTRACT
Most studies of coronavirus disease 2019 (COVID-19) progression have focused on the transfer of patients within secondary or tertiary care hospitals from regular wards to intensive care units. Little is known about the risk factors predicting the progression to severe COVID-19 among patients in community isolation, who are either asymptomatic or suffer from only mild to moderate symptoms. Using a multivariable competing risk survival analysis, we identify several important predictors of progression to severe COVID-19-rather than to recovery-among patients in the largest community isolation center in Wuhan, China from 6 February 2020 (when the center opened) to 9 March 2020 (when it closed). All patients in community isolation in Wuhan were either asymptomatic or suffered from mild to moderate COVID-19 symptoms. We performed competing risk survival analysis on time-to-event data from a cohort study of all COVID-19 patients (n = 1753) in the isolation center. The potential predictors we investigated were the routine patient data collected upon admission to the isolation center: age, sex, respiratory symptoms, gastrointestinal symptoms, general symptoms, and computed tomography (CT) scan signs. The main outcomes were time to severe COVID-19 or recovery. The factors predicting progression to severe COVID-19 were: male sex (hazard ratio (HR) = 1.29, 95% confidence interval (CI) 1.04-1.58, p = 0.018), young and old age, dyspnea (HR = 1.58, 95% CI 1.24-2.01, p < 0.001), and CT signs of ground-glass opacity (HR = 1.39, 95% CI 1.04-1.86, p = 0.024) and infiltrating shadows (HR = 1.84, 95% CI 1.22-2.78, p = 0.004). The risk of progression was found to be lower among patients with nausea or vomiting (HR = 0.53, 95% CI 0.30-0.96, p = 0.036) and headaches (HR = 0.54, 95% CI 0.29-0.99, p = 0.046). Our results suggest that several factors that can be easily measured even in resource-poor settings (dyspnea, sex, and age) can be used to identify mild COVID-19 patients who are at increased risk of disease progression. Looking for CT signs of ground-glass opacity and infiltrating shadows may be an affordable option to support triage decisions in resource-rich settings. Common and unspecific symptoms (headaches, nausea, and vomiting) are likely to have led to the identification and subsequent community isolation of COVID-19 patients who were relatively unlikely to deteriorate. Future public health and clinical guidelines should build on this evidence to improve the screening, triage, and monitoring of COVID-19 patients who are asymtomatic or suffer from mild to moderate symptoms.
ABSTRACT
Once challenged by the SARS-CoV-2 virus, the human host immune system triggers a dynamic process against infection. We constructed a simplistic mathematical model to describe host innate and adaptive immune response to viral challenge. Based on the dynamic properties of viral load and immune response, we classified the resulting dynamics into four modes, corresponding to the increasing severity of COVID-19 disease. We found immune efficacy against viral attack, clearance of infected cells, and IL-6 levels to be prognostic determinants, especially for severe and critical patients. We also investigated vaccine-induced protection against SARS-CoV-2 infection. Results strongly suggested that immune efficacy based on memory T cells, as well as neutralizing antibody titers, could be true indicators of vaccine protection rates. Finally, we analyzed infection dynamics of SARS-CoV-2 variants within the construct of our mathematical model. Overall, our results provide a systematic framework for understanding the dynamics of host response upon challenge by SARS-CoV-2 infection, and this framework can be used to predict vaccine protection and perform clinical diagnosis.
Subject(s)
COVID-19ABSTRACT
Cellular immunity may be involved in organ damage and rehabilitation in patients with coronavirus disease 2019 (COVID-19). We aimed to delineate immunological features of COVID-19 patients with pulmonary sequelae (PS) one year after discharge. 50 COVID-19 survivors were recruited and classified according to radiological characteristics: 24 patients with PS and 26 patients without PS. Phenotypic and functional characteristics of immune cells were evaluated by multiparametric flow cytometry. Patients with PS had an increased proportion of natural killer (NK) cells and lower percentage of B cells compared to patients without PS. Phenotypic and functional features of T cells in patients with PS were predominated by the accumulation of CD4+ T cells secreting IL-17A, short-lived effector-like CD8+ T cells (CD27-CD62L-) and senescent T cells with excessive secretion of granzyme-B/perforin/IFN-{gamma}. NK cells were characterized by the excessive secretion of granzyme-B and perforin and the downregulation of NKP30 and NKP46; highly activated NKT and {gamma}{delta} T cells exhibited NKP30 and TIM-3 upregulation and NKB1 downregulation in patients with PS. However, immunosuppressive cells were comparable between the two groups. The interrelation of immune cells in COVID-19 was intrinsically identified, whereby T cells secreting IL-2, IL-4 and IL-17A were enriched among CD28+ and CD57- cells and cells secreting perforin/granzyme-B/IFN-{gamma}/TNF- expressed markers of terminal differentiation. CD57+NK cells, CD4+perforin+ T cells and CD8+CD27+CD62L+ T cells were identified as the independent predictors for residual lesions. Overall, our findings unveil the profound imbalance of immune landscape that may correlate with organ damage and rehabilitation in COVID-19.
Subject(s)
Pulmonary Embolism , COVID-19ABSTRACT
Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.
Subject(s)
COVID-19ABSTRACT
Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients' data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of na\"ive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.
Subject(s)
COVID-19ABSTRACT
Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c. Our study indicated that ORF9c enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle. One-sentence summarySARS-CoV-2 ORF9c is the first human coronavirus protein localized to membrane, suppressing antiviral response, resembling full viral infection.
Subject(s)
COVID-19ABSTRACT
There is an urgent need to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) that leads to COVID-19 and respiratory failure. Our study is to discover differentially expressed genes (DEGs) and biological signaling pathways by using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE150819 datasets were originally produced using an Illumina NextSeq 500 (Homo sapiens). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) were utilized to identify functional categories and significant pathways. KEGG and GO results suggested that the Cytokine-cytokine receptor interaction, P53 signaling pathway, and Apoptosis are the main signaling pathways in SARS-CoV-2 infected human bronchial organoids (hBOs). Furthermore, NFKBIA, C3, and CCL20 may be key genes in SARS-CoV-2 infected hBOs. Therefore, our study provides further insights into the therapy of COVID-19.
Subject(s)
Coronavirus Infections , Severe Acute Respiratory Syndrome , COVID-19 , Respiratory InsufficiencyABSTRACT
The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues. HIGHLIGHTSO_LICharacterization of 5336 regulated proteins out of 11,394 quantified proteins in the lung, spleen, liver, kidney, heart, thyroid and testis autopsies from 19 patients died from COVID-19. C_LIO_LICTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. C_LIO_LIEvidence for suppression of glucose metabolism in the spleen, liver and kidney; suppression of fatty acid metabolism in the kidney; enhanced fatty acid metabolism in the lung, spleen, liver, heart and thyroid from COVID-19 patients; enhanced protein translation initiation in the lung, liver, renal medulla and thyroid. C_LIO_LITentative model for multi-organ injuries in patients died from COVID-19: SARS-CoV-2 infection triggers hyperinflammatory which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart, kidney and thyroid. C_LIO_LITesticular injuries in COVID-19 patients included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. C_LI
Subject(s)
COVID-19ABSTRACT
There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988). HighlightsO_LIFull-length SARS-CoV-2 prefusion spike with Matrix-M1 (NVX-CoV2373) vaccine. C_LIO_LIInduced hACE2 receptor blocking and neutralizing antibodies in macaques. C_LIO_LIVaccine protected against SARS-CoV-2 replication in the nose and lungs. C_LIO_LIAbsence of pulmonary pathology in NVX-CoV2373 vaccinated macaques. C_LI
Subject(s)
COVID-19 , Lung DiseasesABSTRACT
Background: 2019 Novel coronavirus disease (COVID-19) is turning into a pandemic globally lately. There were few reports illustrated the expression of Angiotensin II (AngII) in COVID-19. This study aimed to demonstrate the expression of AngII in COVID-19 and how it correlated to the disease.Methods and Results: We enrolled 55 patients with COVID-19 admitted to Renmin Hospital of Wuhan University from January 21st to February 21st, 2020. Demographic data were collected upon admission. COVID-19 nuclear acid, plasma AngII, Renin and aldosterone in the lying position without sodium restriction, and other laboratory indicators were together measured by the laboratory department of our hospital. Of the 55 patients with COVID-19, 34(61.8%) had an increased level of AngII. The severity of COVID-19 and male is positively related with the level of AngII. The level of blood lymphocyte, PCT, ALT, and AST were remarkably severe with those of normal level of AngII (P < 0.05). CD4/CD8 cells ratio was significantly higher than those of normal level of AngII (P < 0.05). The results of binary logistic regression analysis showed that the severity of COVID-19 (OR=4.123) and CD4/CD8 ratio(OR=4.050) were the co-directional impact factor while female(OR=0.146) was inverse impact factor of elevated AngII level.Conclusion: High rate of increased level of AngII and its gender differences were detected in COVID-19 patients. Elevated AngII level were correlated with the severity of COVID-19 and CD4/CD8 ratio.
Subject(s)
COVID-19ABSTRACT
Background: 2019 Novel coronavirus disease (COVID-19) is turning into a pandemic globally lately. Angiotensin-converting enzyme 2 (ACE2) is identified as an important functional receptor for SARS-Cov-2. ACE2 and ACE are homologues with inverse functions in the renin-angiotensin system. ACE converts angiotensin I into a vital vasoactive peptide called angiotensin II(AngII), whereas ACE2 hydrolyzes AngII into a series of vasodilators. There were few reports illustrated the expression of AngII in COVID-19. This study aimed to demonstrate the expression of angiotensin II in COVID-19 and how it correlated to the disease. Methods: We enrolled 55 patients with COVID-19 admitted to renmin Hospital of Wuhan University from January 21st to February 21st, 2020. Demographic data were collected upon admission. COVID-19 nuclear acid, plasma AngII, Renin and aldosterone in the lying position without sodium restriction, and other laboratory indicators were together measured by the laboratory department of our hospital. Findings: Of the 55 patients with COVID-19, 34(61.8%) had an increased level of AngII. The severity of COVID-19 and male is positively related with the level of AngII. The level of blood lymphocyte, PCT, ALT, and AST were remarkably severe with those of normal level of AngII (P < 0.05). CD4/CD8 cells ratio was significantly higher whereas CD3+CD8+ cells amount, CD3+CD8+ cells proportion, CD56+CD16+CD3- cells amount and CD19+CD3- cells amount were considerably lower than those of normal level of AngII (P < 0.05). Abnormal rates of blood lymphocyte and PCT were significantly higher in Patients with elevated AngII level. The results of binary logistic regression analysis showed that the severity of COVID-19 (OR=4.123) and CD4/CD8 ratio(OR=4.050) were the co-directional impact factor while female(OR=0.146) was inverse impact factor of elevated AngII level. Interpretation: High rate of increased level of AngII was detected in COVID-19 patients. Patients with elevated AngII level were more likely to be critically ill with COVID-19. Considering the gender differences in ACE2 expression and no gender differences in angiotensin expression, the gender differences in AngII level might indicate less loss of ACE2 in female patients. Elevated AngII level was correlated with CD4/CD8 ratio, suggesting it might involve in immune disorder. Keywords: 2019 Novel coronavirus disease(COVID-19), Angiotensin-converting enzyme 2 (ACE2), Angiotensin II(AngII), gender differences